TNFRSF18
Chr 1TNF receptor superfamily member 18
Also known as: AITR, CD357, ENERGEN, GITR, GITR-D
The protein is a TNF receptor superfamily member that regulates T-cell activation, immune tolerance through regulatory T cells, and T-cell receptor-mediated cell death via NF-kappa-B signaling. This gene is extremely intolerant to loss-of-function mutations (pLI near 1.0), indicating that haploinsufficiency likely causes severe disease, though specific clinical phenotypes associated with TNFRSF18 mutations have not been well-established in humans. Given its critical role in immune regulation, mutations would be expected to cause primary immunodeficiency or autoimmune disorders.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
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
246 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 | 124 | 0 | 124 |
Likely Pathogenic | 0 | 0 | 6 | 0 | 6 |
VUS | 0 | 65 | 23 | 0 | 88 |
Likely Benign | 0 | 15 | 1 | 4 | 20 |
Benign | 0 | 0 | 1 | 0 | 1 |
| Total | 0 | 80 | 155 | 4 | 239 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TNFRSF18 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
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