MAP3K21
Chr 1mitogen-activated protein kinase kinase kinase 21
Also known as: MLK4, dJ862P8.3
MAP3K21 encodes a protein kinase that negatively regulates TLR4 signaling pathways and does not activate the typical JNK, p38, or ERK signaling cascades. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.689), suggesting mutations would likely cause severe developmental phenotypes, though specific disease associations have not yet been established. The inheritance pattern for potential MAP3K21-related disorders has not been determined.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. 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.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
MAP3K21 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
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 →No open access results found
External Resources
Links to major genomics databases and tools