TNFRSF10A

Chr 8

TNF receptor superfamily member 10a

Also known as: APO2, CD261, DR4, TRAILR-1, TRAILR1

NCBI Gene: 8797ENSG00000104689UniProt: O00220

The protein functions as a death receptor that binds TNFSF10/TRAIL ligand and initiates apoptosis through caspase-8 activation and formation of the death-inducing signaling complex. Mutations cause autosomal dominant aplastic anemia and immunodeficiency syndrome characterized by bone marrow failure, recurrent infections, and variable immune system dysfunction. This gene shows very low constraint against loss-of-function variants (high LOEUF score), suggesting tolerance to protein disruption in the general population.

Summary from RefSeq, UniProt
Research Assistant →
1
Active trials
11
Pubs (1 yr)
82
P/LP submissions
0%
P/LP missense
1.56
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— TNFRSF10A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
82 unique Pathogenic / Likely Pathogenic· 90 VUS of 214 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.56LOEUF
pLI 0.000
Z-score -0.34
OE 1.08 (0.77–1.56)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.65Z-score
OE missense 1.11 (1.01–1.23)
291 obs / 261.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE1.08 (0.77–1.56)
0≤0.351.4
Missense OE1.11 (1.01–1.23)
0≤0.61.4
Synonymous OE1.13
0≤1.21.6
LoF obs/exp: 21 / 19.4Missense obs/exp: 291 / 261.6Syn Z: -1.06
DN
0.6937th %ile
GOF
0.79top 10%
LOF
0.2873th %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

214 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic78
Likely Pathogenic4
VUS90
Likely Benign14
Benign12
78
Pathogenic
4
Likely Pathogenic
90
VUS
14
Likely Benign
12
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
78
0
78
Likely Pathogenic
0
0
4
0
4
VUS
0
87
3
0
90
Likely Benign
0
8
2
4
14
Benign
1
3
4
4
12
Total198918198

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

View in ClinVar →

Protein Context — Lollipop Plot

TNFRSF10A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
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
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