TNFAIP3

Chr 6AD

TNF alpha induced protein 3

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

NCBI Gene: 7128ENSG00000118503UniProt: P21580OMIM: 191163

This gene encodes a ubiquitin-editing enzyme that terminates NF-kappa-B inflammatory signaling pathways by deubiquitinating key proteins like RIPK1, TRAF6, and MALT1 in response to cytokines such as TNF and IL-1 beta. Mutations cause autoinflammatory syndrome, familial, Behcet-like 1, which follows an autosomal dominant inheritance pattern. The protein functions as an essential component in controlling immune and inflammatory responses by ensuring these signaling pathways remain transient rather than sustained.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.201 OMIM phenotype
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.
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ClinVar Variants
69 unique Pathogenic / Likely Pathogenic· 297 VUS of 600 total submissions
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Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — TNFAIP3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
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
1.45Z-score
OE missense 0.81 (0.75–0.88)
387 obs / 476.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.06 (0.02–0.20)
0≤0.351.4
Missense OE0.81 (0.75–0.88)
0≤0.61.4
Synonymous OE0.85
0≤1.21.6
LoF obs/exp: 2 / 32.2Missense obs/exp: 387 / 476.2Syn Z: 1.55
DN
0.2898th %ile
GOF
0.3887th %ile
LOF
0.72top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 91% of P/LP variants are LoF · LOEUF 0.20

Literature Evidence

LOFIn addition, 1 of 24 patients with a 6q deletion had an inactivating somatic mutation in TNFAIP3, another negative regulator of NF-kappa-B. Monoallelic deletions of chromosome 6q23, including the TNFAIP3 gene, were identified in 38% of patients, suggesting that haploinsufficiency can predispose to tPMID:19351844

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51
Likely Pathogenic18
VUS297
Likely Benign207
Benign6
Conflicting7
51
Pathogenic
18
Likely Pathogenic
297
VUS
207
Likely Benign
6
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
46
1
4
0
51
Likely Pathogenic
17
0
1
0
18
VUS
5
277
13
2
297
Likely Benign
0
24
46
137
207
Benign
0
1
1
4
6
Conflicting
—7
Total6830365143586

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
IL-23 production in human macrophages is regulated negatively by tumor necrosis factor alpha-induced protein 3 and positively by specificity protein 1 after stimulation of the toll-like receptor 7/8 signaling pathway
Yamaguchi R et al.·Heliyon
2022
TNFAIP3 mutation causing haploinsufficiency of A20 with a hemophagocytic lymphohistiocytosis phenotype: a report of two cases
Aslani N et al.·Pediatr Rheumatol Online J
2022Cohort
TNFAIP3 mutation may be associated with favorable overall survival for patients with T-cell lymphoma
Chen C et al.·Cancer Cell Int
2021Cohort
Identification of ferroptosis related biomarkers and immune infiltration in Parkinson's disease by integrated bioinformatic analysis
Xing N et al.·BMC Med Genomics
2023
Integrated bioinformatics identifies ferroptosis biomarkers and therapeutic targets in idiopathic pulmonary arterial hypertension
Zhang Y et al.·Sci Rep
2025
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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