TNFSF12

Chr 17

TNF superfamily member 12

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

NCBI Gene: 8742 ENSG00000239697 UniProt: O43508 OMIM: 602695

TNFSF12 encodes a cytokine that binds to the FN14 receptor and mediates NF-kappa-B activation, promotes angiogenesis and endothelial cell proliferation, and induces inflammatory cytokines and apoptosis in certain cell types. The gene is highly constrained against loss-of-function variants (pLI 0.77, LOEUF 0.41), but no Mendelian diseases have been definitively associated with TNFSF12 mutations to date. This gene may be a candidate for neurovascular or neuroinflammatory conditions given its role in angiogenesis and cytokine signaling.

OMIM ResearchSummary from RefSeq, UniProt

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

15 unique Pathogenic / Likely Pathogenic· 163 VUS of 299 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

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 OE0.18 (0.09–0.41)

0≤0.351.4

Missense OE0.79 (0.69–0.91)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 4 / 22.4Missense obs/exp: 137 / 173.4Syn Z: -0.33

ClinVar Variant Classifications

299 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

VUS163

Likely Benign108

Benign12

Conflicting1

Pathogenic

163

VUS

108

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	15	0	15
Likely Pathogenic	0	0	0	0	0
VUS	9	134	18	2	163
Likely Benign	0	0	42	66	108
Benign	0	0	6	6	12
Conflicting	—				1
Total	9	134	81	74	299

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

View in ClinVar →

Protein Context — Lollipop Plot

TNFSF12 · 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

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Cardiovascular DiseaseFrailty

Investigating the Combined Effects of Protein, Blueberries, and Exercise on Cardiovascular Health and Frailty in Older Nova Scotians

NOT YET RECRUITING

NCT06693271Phase NANova Scotia Health AuthorityStarted 2025-01-01

intervention of protein, blueberriesExercise training

Prediabetes

Effects of Autonomic Nervous System Modulation by Heart Rate Variability Biofeedback Training With Resonant Frequency Breathing on Glucose Metabolism in Individuals With Prediabetes

RECRUITING

NCT06739993Phase NAJohannes Gutenberg University MainzStarted 2025-05-14

Resonance frequency breathing with heart rate variability biofeedback trainingAnti-Stress program

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Role of inflammatory cytokine in mediating the effect of plasma lipidome on epilepsy: a mediation Mendelian randomization study

Wang X et al.·Front Neurol

2024