MAPK12
Chr 22mitogen-activated protein kinase 12
Also known as: ERK-6, ERK3, ERK6, MAPK 12, P38GAMMA, PRKM12, SAPK-3, SAPK3
MAPK12 encodes p38-gamma, a serine/threonine kinase that transduces extracellular stress signals and inflammatory cytokine responses, playing essential roles in myoblast differentiation, cell cycle regulation, and DNA damage repair. Pathogenic variants cause autosomal recessive developmental and epileptic encephalopathy with microcephaly and simplified gyral pattern, typically presenting in early infancy with severe developmental delays and intractable seizures. The gene shows no intolerance to loss-of-function variants in the general population (pLI near zero), consistent with a recessive inheritance pattern where heterozygous carriers are unaffected.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative 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
237 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 | 140 | 0 | 140 |
Likely Pathogenic | 0 | 0 | 3 | 0 | 3 |
VUS | 0 | 71 | 11 | 0 | 82 |
Likely Benign | 0 | 1 | 0 | 0 | 1 |
Benign | 0 | 0 | 1 | 0 | 1 |
Conflicting | — | 1 | |||
| Total | 0 | 72 | 155 | 0 | 228 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
MAPK12 · 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
External Resources
Links to major genomics databases and tools