MAPK12

Chr 22

mitogen-activated protein kinase 12

Also known as: ERK-6, ERK3, ERK6, MAPK 12, P38GAMMA, PRKM12, SAPK-3, SAPK3

NCBI Gene: 6300 ENSG00000188130 UniProt: P53778 OMIM: 602399

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.

OMIM ResearchSummary from RefSeq, UniProt

Activation of members of the mitogen-activated protein kinase family is a major mechanism for transduction of extracellular signals. Stress-activated protein kinases are one subclass of MAP kinases. The protein encoded by this gene functions as a signal transducer during differentiation of myoblasts to myotubes. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.99

Clinical Summary— MAPK12

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 72 VUS of 84 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.000

Z-score 1.59

OE 0.62 (0.41–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.47Z-score

OE missense 1.09 (0.98–1.21)

234 obs / 214.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.62 (0.41–0.99)

0≤0.351.4

Missense OE?1.09 (0.98–1.21)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 13 / 20.8Missense obs/exp: 234 / 214.8Syn Z: -1.60

This gene — mechanism propensity

0.6840th %ile

GOF

0.6639th %ile

LOF

0.3163th %ile

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.

DNprediction above median

GOFprediction above median

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

84 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS72

Likely Benign1

Conflicting1

Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	0	71	1	0	72
Likely Benign	0	1	0	0	1
Benign	0	0	0	0	0
Conflicting	—				1
Total	0	72	2	0	75

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

View in ClinVar →

143 pathogenic / likely-pathogenic (of 154) ClinVar copy-number / structural variants overlap MAPK12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →