TNFSF10

Chr 3

TNF superfamily member 10

Also known as: APO2L, Apo-2L, CD253, TANCR, TL2, TNLG6A, TRAIL

NCBI Gene: 8743ENSG00000121858UniProt: P50591OMIM: 603598

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues. This protein binds to several members of TNF receptor superfamily including TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and possibly also to TNFRSF11B/OPG. The activity of this protein may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and TNFRSF11B/OPG that cannot induce apoptosis. The binding of this protein to its receptors has been shown to trigger the activation of MAPK8/JNK, caspase 8, and caspase 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

OMIMResearchGenerating clinical summary…
DNmechanismLOEUF 0.64
Clinical Summary— TNFSF10
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
35 VUS of 57 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?
0.64LOEUF
pLI 0.135
Z-score 2.51
OE 0.28 (0.14–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
0.17Z-score
OE missense 0.96 (0.84–1.10)
142 obs / 147.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.28 (0.14–0.64)
0≤0.351.4
Missense OE?0.96 (0.84–1.10)
0≤0.61.4
Synonymous OE?0.97
0≤1.21.6
LoF obs/exp: 4 / 14.2Missense obs/exp: 142 / 147.7Syn Z: 0.15

This gene — mechanism propensity

DN
0.7230th %ile
GOF
0.4579th %ile
LOF
0.3163th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

57 submitted variants in ClinVar

ClinVar

Classification Summary

VUS35
Likely Benign3
Benign7
35
VUS
3
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
0
0
0
0
VUS
0
35
0
0
35
Likely Benign
0
2
0
1
3
Benign
0
1
4
2
7
Total0384345

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap TNFSF10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TNFSF10 · 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

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients