TNFRSF25

Chr 1

TNF receptor superfamily member 25

Also known as: APO-3, DDR3, DR3, LARD, TNFRSF12, TR3, TRAMP, WSL-1

NCBI Gene: 8718ENSG00000215788UniProt: Q93038

This protein is a TNF-receptor superfamily member that mediates NF-kappa B activation, induces apoptosis, and regulates lymphocyte homeostasis by serving as a receptor for TNFSF12/TWEAK. Mutations in TNFRSF25 cause autosomal dominant immunodeficiency with susceptibility to viral infections and autoimmune manifestations. The gene is expressed preferentially in lymphoid tissues and plays a critical role in removing self-reactive T cells in the thymus.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
16
Pubs (1 yr)
54
P/LP submissions
0%
P/LP missense
0.60
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— TNFRSF25
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
54 unique Pathogenic / Likely Pathogenic· 57 VUS of 142 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
1.57Z-score
OE missense 0.74 (0.66–0.83)
205 obs / 278.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.33 (0.19–0.60)
0≤0.351.4
Missense OE0.74 (0.66–0.83)
0≤0.61.4
Synonymous OE0.88
0≤1.21.6
LoF obs/exp: 8 / 24.1Missense obs/exp: 205 / 278.7Syn Z: 1.01
DN
0.7228th %ile
GOF
0.79top 10%
LOF
0.2289th %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
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.

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

ClinVar Variant Classifications

142 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53
Likely Pathogenic1
VUS57
Likely Benign11
Benign7
53
Pathogenic
1
Likely Pathogenic
57
VUS
11
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
53
0
53
Likely Pathogenic
0
0
1
0
1
VUS
0
50
7
0
57
Likely Benign
0
4
1
6
11
Benign
0
1
2
4
7
Total0556410129

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

View in ClinVar →

Protein Context — Lollipop Plot

TNFRSF25 · 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
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
Pretransplant targeting of TNFRSF25 and CD25 stimulates recipient Tregs in target tissues, ameliorating GVHD post-HSCT.
McManus D et al.·Blood
2025Open Access
Brain-derived exosomes from aged mice accelerate cognitive decline in repeated mild traumatic brain injury by activating neuronal Tnfrsf25.
Liu Y et al.·Exp Gerontol
2025
Targeting TNFRSF25 by agonistic antibodies and multimeric TL1A proteins co-stimulated CD8+ T cells and inhibited tumor growth.
Lyu X et al.·J Immunother Cancer
2024Open Access
Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: Endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival.
Marfil-Garza BA et al.·Am J Transplant
2022
Association between prenatal bisphenol a exposure and promoter hypermethylation of CAPS2, TNFRSF25, and HKR1 genes in cord blood.
Song X et al.·Environ Res
2020
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