TRAF6

Chr 11

TNF receptor associated factor 6

Also known as: MGC:3310, RNF85

NCBI Gene: 7189ENSG00000175104UniProt: Q9Y4K3

This highly constrained gene encodes an E3 ubiquitin ligase that mediates synthesis of polyubiquitin chains and serves as a critical adapter protein in TNF receptor, IL-1 receptor, and IL-17 receptor signaling pathways, ultimately activating NF-kappa-B and JUN to regulate immune responses and osteoclast differentiation. Mutations cause autosomal recessive immunodeficiency with recurrent infections due to impaired innate and adaptive immune function. The gene's extreme intolerance to loss-of-function variants (pLI 0.997, LOEUF 0.217) reflects its essential role in immune system development and function.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
369
Pubs (1 yr)
15
P/LP submissions
0%
P/LP missense
0.22
LOEUF· LoF intol.
LOF
Mechanism· predicted
Clinical Summary— TRAF6
⚡
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
15 unique Pathogenic / Likely Pathogenic· 46 VUS of 77 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — TRAF6
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.22LOEUF
pLI 0.997
Z-score 4.13
OE 0.05 (0.01–0.22)
Highly constrained

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

Missense Constraint
2.72Z-score
OE missense 0.55 (0.49–0.63)
162 obs / 292.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.05 (0.01–0.22)
0≤0.351.4
Missense OE0.55 (0.49–0.63)
0≤0.61.4
Synonymous OE0.94
0≤1.21.6
LoF obs/exp: 1 / 21.9Missense obs/exp: 162 / 292.8Syn Z: 0.45
DN
0.3594th %ile
GOF
0.4184th %ile
LOF
0.71top 10%

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

LOFprediction above median · LOEUF 0.22

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

77 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic1
VUS46
Likely Benign6
Benign1
14
Pathogenic
1
Likely Pathogenic
46
VUS
6
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
14
0
14
Likely Pathogenic
0
0
1
0
1
VUS
0
38
8
0
46
Likely Benign
0
4
0
2
6
Benign
0
0
1
0
1
Total04224268

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

View in ClinVar →

Protein Context — Lollipop Plot

TRAF6 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
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