TNFSF12

Chr 17

TNF superfamily member 12

Also known as: APO3L, DR3LG, TNF12, TNLG4A, TWEAK

NCBI Gene: 8742ENSG00000239697UniProt: O43508OMIM: 602695

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is a ligand for the FN14/TWEAKR receptor. This cytokine has overlapping signaling functions with TNF, but displays a much wider tissue distribution. This cytokine, which exists in both membrane-bound and secreted forms, can induce apoptosis via multiple pathways of cell death in a cell type-specific manner. This cytokine is also found to promote proliferation and migration of endothelial cells, and thus acts as a regulator of angiogenesis. Alternative splicing results in multiple transcript variants. Some transcripts skip the last exon of this gene and continue into the second exon of the neighboring TNFSF13 gene; such read-through transcripts are contained in GeneID 407977, TNFSF12-TNFSF13. [provided by RefSeq, Oct 2010]

OMIMResearchGenerating clinical summary…
LOEUF 0.41
Clinical Summary— TNFSF12
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Gene-Disease Validity (ClinGen)
common variable immunodeficiency · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.77) — some intolerance to loss-of-function variants.
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ClinVar Variants
154 VUS of 275 total submissions
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Clinical Trials
3 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
Moderate LoF intolerance
LoF Constraint?
0.41LOEUF
pLI 0.770
Z-score 3.60
OE 0.18 (0.09–0.41)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?
0.98Z-score
OE missense 0.79 (0.69–0.91)
137 obs / 173.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.18 (0.09–0.41)
0≤0.351.4
Missense OE?0.79 (0.69–0.91)
0≤0.61.4
Synonymous OE?1.05
0≤1.21.6
LoF obs/exp: 4 / 22.4Missense obs/exp: 137 / 173.4Syn Z: -0.33

ClinVar Variant Classifications

275 submitted variants in ClinVar

ClinVar

Classification Summary

VUS154
Likely Benign108
Benign12
Conflicting1
154
VUS
108
Likely Benign
12
Benign
1
Conflicting

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
9
134
9
2
154
Likely Benign
0
0
42
66
108
Benign
0
0
6
6
12
Conflicting
—1
Total91345774275

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap TNFSF12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TNFSF12 · 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