MAPK3

Chr 16

mitogen-activated protein kinase 3

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

NCBI Gene: 5595ENSG00000102882UniProt: P27361

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]

332
ClinVar variants
277
Pathogenic / LP
0.04
pLI score
3
Active trials
Clinical Summary— MAPK3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.
📋
ClinVar Variants
277 Pathogenic / Likely Pathogenic· 42 VUS of 332 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.61LOEUF
pLI 0.037
Z-score 2.80
OE 0.31 (0.17–0.61)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.74Z-score
OE missense 0.68 (0.60–0.78)
164 obs / 239.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.31 (0.17–0.61)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.60–0.78)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.87
0≤1.21.6
LoF obs/exp: 6 / 19.3Missense obs/exp: 164 / 239.8Syn Z: 1.00

ClinVar Variant Classifications

332 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic233
Likely Pathogenic44
VUS42
Likely Benign12
Benign1
233
Pathogenic
44
Likely Pathogenic
42
VUS
12
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
233
0
233
Likely Pathogenic
0
1
43
0
44
VUS
0
29
13
0
42
Likely Benign
0
3
1
8
12
Benign
0
0
0
1
1
Total0332909332

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
📖
GeneReview available — MAPK3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Medicine for chronic atrophic gastritis: a systematic review, meta- and network pharmacology analysis.
Weng J et al.·Ann Med
2023Review
MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis.
Deng R et al.·Autophagy
2021
Molecular mechanisms underlying Tao-Hong-Si-Wu decoction treating hyperpigmentation based on network pharmacology, Mendelian randomization analysis, and experimental verification.
Chen J et al.·Pharm Biol
2024Functional
Identifying the Potential of miRNAs in Houttuynia cordata-Derived Exosome-Like Nanoparticles Against Respiratory RNA Viruses.
Zhu H et al.·Int J Nanomedicine
2023
Gene-level analysis reveals the genetic aetiology and therapeutic targets of schizophrenia.
Dang X et al.·Nat Hum Behav
2025Meta-analysis
Exploring the mechanism of ellagic acid against gastric cancer based on bioinformatics analysis and network pharmacology.
Liu Z et al.·J Cell Mol Med
2023Functional
Removal of hypersignaling endosomes by simaphagy.
Migliano SM et al.·Autophagy
2024
Cbl-b inhibitor NX-1607 activates MAPK/ERK signaling pathway and enhances T-cell activation.
Zhu W et al.·J Immunother Cancer
2025
The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model.
Jiang J et al.·Microbiome
2024Functional
Network toxicological and single-cell sequencing reveals the potential mechanisms of psoriatic toxicity of polybrominated diphenyl ethers.
Yu Q et al.·Ecotoxicol Environ Saf
2025Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Mitogen-Activated Protein Kinase-3 (MAPK3) Is the Main Target of Microsecond Pulsed Electric Field in Human Medulloblastoma.
Bahadorimonfared A et al.·Asian Pac J Cancer Prev
2026
Saccharin Aggravates Eosinophilic Esophagitis via MAPK3 Interaction: A Network Toxicology and Machine Learning Study With SPR Analysis.
Yang Y et al.·Food Sci Nutr
2026🔓 Open Access
MAPK3 modulates enhancer-promoter interactions of SKAP2 in acute myeloid leukemia.
Hu Y et al.·Carcinogenesis
2025
Characterization of rutin bindingto HRAS and MAPK3 and its clinical prognostic relevancein lung cancer: Using in silico and clinical prognostic experimental design.
Kamli H.·Naunyn Schmiedebergs Arch Pharmacol
2026
Identification of Tripeptide Inhibitors Targeting MAPK3 in Leishmania martiniquensis and Leishmania orientalis Using Molecular Modeling, Virtual Screening, Molecular Dynamics, and In Vitro Approach.
Kiriwan D et al.·ACS Omega
2025🔓 Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Acute Myeloid LeukemiaRecurrent Acute Myeloid LeukemiaRefractory Acute Myeloid Leukemia

Entrectinib in Combination With ASTX727 for the Treatment of Relapsed/Refractory TP53 Mutated Acute Myeloid Leukemia

ACTIVE NOT RECRUITING
NCT05396859Phase PHASE1OHSU Knight Cancer InstituteStarted 2022-10-28
Decitabine and CedazuridineEntrectinibLaboratory Biomarker Analysis
Advanced/Metastatic Breast CancerBreast Cancer (Early Breast Cancer)

Praegnant Breast Cancer: Early/Advanced/Metastatic

RECRUITING
NCT02338167University Hospital TuebingenStarted 2014-06
Blood sampling
Metastatic Thyroid Gland CarcinomaUnresectable Thyroid Gland Carcinoma

Dabrafenib and Lapatinib in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed by Surgery

ACTIVE NOT RECRUITING
NCT01947023Phase PHASE1National Cancer Institute (NCI)Started 2013-09-27
Biopsy ProcedureBiospecimen CollectionComputed Tomography

External Resources

Links to major genomics databases and tools