TNFRSF25
Chr 1TNF receptor superfamily member 25
Also known as: APO-3, DDR3, DR3, LARD, TNFRSF12, TR3, TRAMP, WSL-1
The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed preferentially in the tissues enriched in lymphocytes, and it may play a role in regulating lymphocyte homeostasis. This receptor has been shown to stimulate NF-kappa B activity and regulate cell apoptosis. The signal transduction of this receptor is mediated by various death domain containing adaptor proteins. Knockout studies in mice suggested the role of this gene in the removal of self-reactive T cells in the thymus. Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported, most of which are potentially secreted molecules. The alternative splicing of this gene in B and T cells encounters a programmed change upon T-cell activation, which predominantly produces full-length, membrane bound isoforms, and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation. [provided by RefSeq, Jul 2008]
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene — mechanism propensity
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
80 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 | 0 | 0 | 0 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 0 | 50 | 1 | 0 | 51 |
Likely Benign | 0 | 4 | 1 | 6 | 11 |
Benign | 0 | 1 | 1 | 4 | 6 |
| Total | 0 | 55 | 3 | 10 | 68 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →57 pathogenic / likely-pathogenic (of 66) ClinVar copy-number / structural variants overlap TNFRSF25 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →
Protein Context — Lollipop Plot
TNFRSF25 · 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
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools