MAPK1

Chr 22AD

mitogen-activated protein kinase 1

Also known as: ERK, ERK-2, ERK2, ERT1, MAPK2, NS13, P42MAPK, PRKM1

NCBI Gene: 5594 ENSG00000100030 UniProt: P28482 OMIM: 176948

The MAPK1 protein is a serine/threonine kinase that serves as an essential component of the MAP kinase/ERK signaling pathway, regulating cellular processes including proliferation, differentiation, transcription, and development through phosphorylation of diverse nuclear and cytoplasmic substrates. Mutations cause autosomal dominant Noonan syndrome 13, a developmental disorder affecting multiple organ systems. This gene is highly constrained against loss-of-function variants (pLI 0.997, LOEUF 0.175), indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. One study also suggests that this protein acts as a transcriptional repressor independent of its kinase activity. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene. [provided by RefSeq, Jan 2014]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.171 OMIM phenotype

Clinical Summary— MAPK1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 32 VUS of 79 total submissions

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Clinical Trials

2 active or recruiting trials — 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

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.17LOEUF

pLI 0.997

Z-score 3.83

OE 0.00 (0.00–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.61Z-score

OE missense 0.26 (0.20–0.33)

48 obs / 186.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.26 (0.20–0.33)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 0 / 17.1Missense obs/exp: 48 / 186.9Syn Z: -0.49

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateMAPK1-related Noonan syndromeGOFAD

This gene — mechanism propensity

0.4289th %ile

GOF

0.5071th %ile

LOF

0.72top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.17

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.

Literature Evidence

LOFWe demonstrate haplo-insufficient ERK2 expression in patients with a novel ?1 Mb micro-deletion in distal 22q11.2, a region that includes ERK2. These patients exhibit conotruncal and craniofacial anomalies that arise from perturbation of neural crest development and exhibit defects comparable to the1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 18952847 ↗

ClinVar Variant Classifications

79 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic7

VUS32

Likely Benign14

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	5	0	0	5
Likely Pathogenic	0	7	0	0	7
VUS	0	28	3	1	32
Likely Benign	0	2	3	9	14
Benign	0	1	0	2	3
Conflicting	—				1
Total	0	43	6	12	62

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

View in ClinVar →

88 pathogenic / likely-pathogenic (of 112) ClinVar copy-number / structural variants overlap MAPK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →