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…

Primary Disease Associations & Inheritance

Noonan syndrome 13MIM #619087

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Noonan syndrome 13; no ClinGen or GenCC tier

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

576

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.17

LOEUF· LoF intol.

GOF*

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in MAPK1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 420

207 rare PASS variants

Rare truncating (LoF)

1 in 13,000

27 rare PASS variants

Rare synonymous (reference)

1 in 130

188 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MAPK1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 520	1 in 10,000
South Asian	~43k	1 in 660	1 in 8,600
Remaining (unassigned)	~30k	1 in 600	≈ 1 in 20,000
European (Finnish)	~27k	1 in 1,000	≈ 1 in 6,500
Admixed American	~22k	1 in 1,200	1 in 2,200
African / African American	~21k	1 in 600	≈ 1 in 5,300
East Asian	~20k	1 in 1,300	none seen
Ashkenazi Jewish	~13k	≈ 1 in 4,800	none seen
Middle Eastern	~2,884	≈ 1 in 1,400	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 6 of 8 coding exons well covered in gnomAD exomes; exons 1, 8 marginal. Genomes: all 8.? see exons ↓