TNFAIP3

Chr 6

TNF alpha induced protein 3

Also known as: A20, AIFBL1, AISBL, OTUD7C, TNFA1P2

NCBI Gene: 7128ENSG00000118503UniProt: P21580

This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein and ubiqitin-editing enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The encoded protein, which has both ubiquitin ligase and deubiquitinase activities, is involved in the cytokine-mediated immune and inflammatory responses. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2012]

Primary Disease Associations & Inheritance

UniProtAutoinflammatory syndrome, familial, Behcet-like 1
543
ClinVar variants
85
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— TNFAIP3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
85 Pathogenic / Likely Pathogenic· 256 VUS of 543 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.20LOEUF
pLI 1.000
Z-score 4.93
OE 0.06 (0.02–0.20)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
1.45Z-score
OE missense 0.81 (0.75–0.88)
387 obs / 476.2 exp
Tolerant

Mild missense constraint

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.0.06 (0.02–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.75–0.88)
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.0.85
0≤1.21.6
LoF obs/exp: 2 / 32.2Missense obs/exp: 387 / 476.2Syn Z: 1.55

ClinVar Variant Classifications

543 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68
Likely Pathogenic17
VUS256
Likely Benign164
Benign21
Conflicting17
68
Pathogenic
17
Likely Pathogenic
256
VUS
164
Likely Benign
21
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
31
3
34
0
68
Likely Pathogenic
11
0
6
0
17
VUS
5
239
11
1
256
Likely Benign
0
26
35
103
164
Benign
0
6
10
5
21
Conflicting
—17
Total4727496109543

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

View in ClinVar →

Protein Context — Lollipop Plot

TNFAIP3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — TNFAIP3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma.
Shen R et al.·Signal Transduct Target Ther
2023
The Complexity of Being A20: From Biological Functions to Genetic Associations.
Karri U et al.·J Clin Immunol
2024Review
A20 Haploinsufficiency: A Systematic Review of 177 Cases.
Elhani I et al.·J Invest Dermatol
2024Review
Pathogenicity and virulence of Japanese encephalitis virus: Neuroinflammation and neuronal cell damage.
Ashraf U et al.·Virulence
2021Review
Integrated computational analysis identifies therapeutic targets with dual action in cancer cells and T cells.
Luo C et al.·Immunity
2025
TNIP3 protects against pathological cardiac hypertrophy by stabilizing STAT1.
Shi H et al.·Cell Death Dis
2024
Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management.
López-Nevado M et al.·Front Immunol
2021
Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation via Increasing Ubiquitination of NEK7.
Zhou X et al.·Adv Sci (Weinh)
2024
Psoriasis harbors multiple pathogenic type 17 T-cell subsets: Selective modulation by risankizumab.
Kim J et al.·J Allergy Clin Immunol
2025
Circulating Tumor DNA Sequencing for Biologic Classification and Individualized Risk Stratification in Patients With Hodgkin Lymphoma.
Heger JM et al.·J Clin Oncol
2024Cohort
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
Thrombotic Thrombocytopenic Purpura, Acquired

Association of TNFAIP3 With Immune-mediated TTP

ACTIVE NOT RECRUITING
NCT06928233Phase NAFondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoStarted 2025-04-04
blood sampling
Overweight or Obese Adults

Time-Restricted Eating for Weight-Loss Maintenance

RECRUITING
NCT07163455Phase NAHarbin Medical UniversityStarted 2026-01-26
Scheduled Weight Maintenance Nutrition EducationTime-Restricted Eating (10-Hour Window)
Ischemic Stroke

Ischemic Stroke Nutrition Intervention Study

ACTIVE NOT RECRUITING
NCT06817512Phase NAHarbin Medical UniversityStarted 2025-03-23
Vitamin K2Placebo
Recurrent Diffuse Large B-Cell Lymphoma Activated B-Cell TypeRefractory Diffuse Large B-Cell Lymphoma Activated B-Cell Type

Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

ACTIVE NOT RECRUITING
NCT02443077Phase PHASE3National Cancer Institute (NCI)Started 2016-10-12
Autologous Bone Marrow TransplantationAutologous Hematopoietic Stem Cell TransplantationCarmustine

External Resources

Links to major genomics databases and tools