TNFRSF12A

Chr 16

TNF receptor superfamily member 12A

Also known as: CD266, FN14, TWEAKR

NCBI Gene: 51330ENSG00000006327UniProt: Q9NP84

Involved in positive regulation of extrinsic apoptotic signaling pathway and regulation of wound healing. Predicted to be located in cell surface and ruffle. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2025]

61
ClinVar variants
35
Pathogenic / LP
0.02
pLI score
0
Active trials
Clinical Summary— TNFRSF12A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
35 Pathogenic / Likely Pathogenic· 24 VUS of 61 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.53LOEUF
pLI 0.018
Z-score 0.78
OE 0.62 (0.28–1.53)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.14Z-score
OE missense 1.05 (0.85–1.30)
60 obs / 57.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.62 (0.28–1.53)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.05 (0.85–1.30)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.36
0≤1.21.6
LoF obs/exp: 3 / 4.8Missense obs/exp: 60 / 57.0Syn Z: -1.40

ClinVar Variant Classifications

61 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
VUS24
Likely Benign1
Benign1
35
Pathogenic
24
VUS
1
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
35
0
35
Likely Pathogenic
0
0
0
0
0
VUS
0
15
9
0
24
Likely Benign
0
1
0
0
1
Benign
0
0
0
1
1
Total01644161

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

View in ClinVar →

Protein Context — Lollipop Plot

TNFRSF12A · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Integrative single-cell and spatial transcriptomic analyses identify a pathogenic cholangiocyte niche and TNFRSF12A as therapeutic target for biliary atresia.
Xiao MH et al.·Hepatology
2025
Single-Cell Transcriptome Analysis Reveals Inter-Tumor Heterogeneity in Bilateral Papillary Thyroid Carcinoma.
Wang T et al.·Front Immunol
2022
TNFRSF12A expression in stomach adenocarcinoma and its preliminary role in predicting immunotherapy response.
Sun LD et al.·Front Immunol
2025
Bioinformatic identification of important roles of COL1A1 and TNFRSF12A in cartilage injury and osteoporosis.
Liu M et al.·J Int Soc Sports Nutr
2025
Clinical significance and diagnostic value of QPCT, SCEL and TNFRSF12A in papillary thyroid cancer.
Liang T et al.·Pathol Res Pract
2023
Unbiased Single-Cell Sequencing of Hematopoietic and Immune Cells from Aplastic Anemia Reveals the Contributors of Hematopoiesis Failure and Dysfunctional Immune Regulation.
Guo R et al.·Adv Sci (Weinh)
2024Case report
Single-cell profiling uncovers synovial fibroblast subpopulations associated with chondrocyte injury in osteoarthritis.
Liu Z et al.·Front Endocrinol (Lausanne)
2024
Bruceine A derivative P1 alleviates renal inflammation via Tnfrsf12a pathway in diabetic nephropathy.
He J et al.·Int Immunopharmacol
2025
Deciphering Mesenchymal Drivers of Human Dupuytren's Disease at Single-Cell Level.
Dobie R et al.·J Invest Dermatol
2022
Distinct tumor-TAM interactions in IDH-stratified glioma microenvironments unveiled by single-cell and spatial transcriptomics.
Motevasseli M et al.·Acta Neuropathol Commun
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools