MAP3K8
Chr 10mitogen-activated protein kinase kinase kinase 8
Also known as: AURA2, COT, EST, ESTF, MEKK8, TPL2, Tpl-2, c-COT
MAP3K8 encodes a serine/threonine protein kinase that activates MAPK/ERK and JNK signaling pathways and is required for TLR4-mediated inflammatory responses, T-helper cell differentiation, and cytokine production including TNF-alpha and interleukin-8. The gene is highly constrained against loss-of-function variants, but no Mendelian pediatric disorders have been definitively associated with germline MAP3K8 mutations. Somatic mutations in this gene contribute to lung cancer development.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Moderately missense-constrained (top ~2.5%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
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
297 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 9 | 0 | 9 |
Likely Pathogenic | 0 | 0 | 1 | 0 | 1 |
VUS | 1 | 129 | 12 | 2 | 144 |
Likely Benign | 0 | 1 | 29 | 77 | 107 |
Benign | 0 | 1 | 15 | 8 | 24 |
| Total | 1 | 131 | 66 | 87 | 285 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
MAP3K8 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools