MAPK3

Chr 16

mitogen-activated protein kinase 3

Also known as: ERK-1, ERK1, ERT2, HS44KDAP, HUMKER1A, P44ERK1, P44MAPK, PRKM3

NCBI Gene: 5595 ENSG00000102882 UniProt: P27361 OMIM: 601795

MAPK3 encodes ERK1, a serine/threonine kinase that phosphorylates nuclear and cytoplasmic substrates to regulate cell proliferation, differentiation, and survival as part of the MAPK/ERK signaling cascade. Mutations cause a neurodevelopmental disorder with intellectual disability, seizures, and distinctive facial features, following an autosomal dominant inheritance pattern. The gene shows moderate constraint to loss-of-function variation (LOEUF 0.614), and a GeneReviews entry is available for detailed clinical guidance.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. This kinase is activated by upstream kinases, resulting in its translocation to the nucleus where it phosphorylates nuclear targets. Alternatively spliced transcript variants encoding different protein isoforms have been described. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.61

Clinical Summary— MAPK3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 30 VUS of 59 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MAPK3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.037

Z-score 2.80

OE 0.31 (0.17–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.74Z-score

OE missense 0.68 (0.60–0.78)

164 obs / 239.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.17–0.61)

0≤0.351.4

Missense OE?0.68 (0.60–0.78)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 6 / 19.3Missense obs/exp: 164 / 239.8Syn Z: 1.00

This gene — mechanism propensity

0.7227th %ile

GOF

0.6931th %ile

LOF

0.3744th %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

59 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS30

Likely Benign13

Benign1

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	1	0	0	1
VUS	1	29	0	0	30
Likely Benign	0	3	1	9	13
Benign	0	0	0	1	1
Total	1	33	1	10	45

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

View in ClinVar →

280 pathogenic / likely-pathogenic (of 300) ClinVar copy-number / structural variants overlap MAPK3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →