MAPK3
Chr 16mitogen-activated protein kinase 3
Also known as: ERK-1, ERK1, ERT2, HS44KDAP, HUMKER1A, P44ERK1, P44MAPK, PRKM3
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.
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 (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
354 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 | 234 | 0 | 234 |
Likely Pathogenic | 0 | 1 | 43 | 0 | 44 |
VUS | 1 | 29 | 12 | 0 | 42 |
Likely Benign | 0 | 3 | 1 | 9 | 13 |
Benign | 0 | 0 | 0 | 1 | 1 |
| Total | 1 | 33 | 290 | 10 | 334 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
MAPK3 · 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
Entrectinib in Combination With ASTX727 for the Treatment of Relapsed/Refractory TP53 Mutated Acute Myeloid Leukemia
ACTIVE NOT RECRUITINGDabrafenib and Lapatinib in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed by Surgery
ACTIVE NOT RECRUITINGPraegnant Breast Cancer: Early/Advanced/Metastatic
RECRUITINGExternal Resources
Links to major genomics databases and tools