TNFRSF4
Chr 1ARTNF receptor superfamily member 4
Also known as: ACT35, CD134, IMD16, OX40, TXGP1L
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.
Primary Disease Associations & Inheritance
Limited evidence — not for standalone diagnostic reporting
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
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.
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.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
499 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 104 | 0 | 104 |
Likely Pathogenic | 0 | 0 | 6 | 0 | 6 |
VUS | 16 | 149 | 43 | 4 | 212 |
Likely Benign | 1 | 8 | 56 | 83 | 148 |
Benign | 0 | 1 | 11 | 7 | 19 |
Conflicting | — | 5 | |||
| Total | 17 | 158 | 220 | 94 | 494 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TNFRSF4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Neoadjuvant INBRX-106 in Combination With Pembrolizumab for Stage II/III TNBC Patients
RECRUITINGStudy of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
ACTIVE NOT RECRUITINGA Pilot Study of Fenofibrate to Prevent Kidney Function Loss in Type 1 Diabetes
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools