GeneBe

MAPK1

protein-coding

mitogen-activated protein kinase 1, the group of Mitogen-activated protein kinases

Gene summary

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]

Previous symbols:
  • PRKM2
  • PRKM1

MANE transcript

NM_002745.5

Inheritance

AD

ClinVar variants

P:13U:41B:14

Top phenotype

Noonan syndrome 13

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr22:21,759,657-21,867,680

External References & Databases

Ensembl (ENSG00000100030)NCBI Gene (5594)OMIM (176948)HGNC:6871GenCCUniProt (P28482)AlphaFoldClinVar (MAPK1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~108.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Noonan syndrome 13MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033669

Submitter: G2P

Noonan syndrome 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033669

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Noonan syndrome 13AD

Manifestation: Cardiovascular; Dental; Craniofacial; Hematologic; Musculoskeletal; Neurologic

Intervention: Cardiovascular; Hematologic

Rationale: Among other findings, the condition can include congenital heart anomalies such as valvular abnormalities, and awareness may allow early diagnosis and management; Bleeding diathesis has been described, and awareness may allow preventative measures and early management of acute and chronic hematologic issues

Refs: 32721402Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAPK1 variants in ClinVar

13 Conditions Cataloged
not providedTotal: 41
Noonan syndrome 13Total: 19
MAPK1-related disorderTotal: 16
not specifiedTotal: 8
Specific learning disabilityTotal: 7
Abnormal facial shapeTotal: 7
Atypical behaviorTotal: 7
Intellectual disabilityTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002745.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
10
clinvar
2
clinvar
 14
missense
5
clinvar
8
clinvar
34
clinvar
2
clinvar
 49
nonsense
0
start loss
1
clinvar
 1
frameshift
0
splice donor/acceptor (+/-2bp)
4
clinvar
 4
Total584112268

Highest pathogenic variant AF is 0.0000043474965

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002745.5RefSeqNP_002736.38MANE Select
ENST00000215832.11EnsemblENSP00000215832.78MANE Select
NM_138957.3RefSeqNP_620407.18Standard
ENST00000398822.7EnsemblENSP00000381803.38Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
mapk1Danio rerio

Structure: pericardial cavity

Quality: edematous

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics
  • Prion diseases - Homo sapiens (human)
  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Non-small cell lung cancer - Homo sapiens (human)
  • Platelet activation - Homo sapiens (human)

Biological Process

  • MAPK cascade
  • activation of MAPK activity
  • protein phosphorylation
  • apoptotic process
  • chemotaxis

Molecular Function

  • phosphotyrosine residue binding
  • DNA binding
  • protein serine/threonine kinase activity
  • MAP kinase activity
  • MAP kinase kinase activity

Cellular Component

  • extracellular region
  • nucleus
  • nucleoplasm
  • cytoplasm
  • mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000215832
Coding exons
8
Length
113182
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.61481870.2570.000009422386
Missense (PolyPhen)772.9230.095991918
Synonymous-0.4887166.01.080.00000325651
Loss of Function3.83017.10.008.32e-7222

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in respons to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Phosphorylates CDK2AP2 (By similarity). {ECO:0000250|UniProtKB:P63086, ECO:0000269|PubMed:10617468, ECO:0000269|PubMed:10637505, ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:12110590, ECO:0000269|PubMed:12356731, ECO:0000269|PubMed:12792650, ECO:0000269|PubMed:12794087, ECO:0000269|PubMed:12974390, ECO:0000269|PubMed:15184391, ECO:0000269|PubMed:15241487, ECO:0000269|PubMed:15616583, ECO:0000269|PubMed:15664191, ECO:0000269|PubMed:15788397, ECO:0000269|PubMed:15952796, ECO:0000269|PubMed:16581800, ECO:0000269|PubMed:18794356, ECO:0000269|PubMed:19265199, ECO:0000269|PubMed:19879846, ECO:0000269|PubMed:22033920, ECO:0000269|PubMed:7588608, ECO:0000269|PubMed:8622688, ECO:0000269|PubMed:9480836, ECO:0000269|PubMed:9596579, ECO:0000269|PubMed:9649500, ECO:0000269|PubMed:9687510, ECO:0000303|PubMed:15526160, ECO:0000303|PubMed:16393692, ECO:0000303|PubMed:19565474, ECO:0000303|PubMed:21779493}.;

Recessive Scores

pRec
0.983

Intolerance Scores

RVIS EVS
-0.41
RVIS percentile EVS
26.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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