GeneBe

MAPKAPK5

protein-coding

MAPK activated protein kinase 5, the group of MAPK activated protein kinases

Gene summary

The protein encoded by this gene is a tumor suppressor and member of the serine/threonine kinase family. In response to cellular stress and proinflammatory cytokines, this kinase is activated through its phosphorylation by MAP kinases including MAPK1/ERK, MAPK14/p38-alpha, and MAPK11/p38-beta. The encoded protein is found in the nucleus but translocates to the cytoplasm upon phosphorylation and activation. This kinase phosphorylates heat shock protein HSP27 at its physiologically relevant sites. Two alternately spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2012]

MANE transcript

NM_003668.4

Inheritance

AR

ClinVar variants

P:6U:68B:7

Top phenotype

Neurocardiofaciodigital syndrome

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr12:111,842,013-111,902,222

External References & Databases

Ensembl (ENSG00000089022)NCBI Gene (8550)OMIM (606723)HGNC:6889GenCCUniProt (Q8IW41)AlphaFoldClinVar (MAPKAPK5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~60.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurocardiofaciodigital syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859247

Submitter: G2P

neurocardiofaciodigital syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859247

Submitter: Ambry Genetics

neurocardiofaciodigital syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859247

Submitter: PanelApp Australia

neurocardiofaciodigital syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859247

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neurocardiofaciodigital syndromeAR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 33442026; 35575217; 36581449Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAPKAPK5 variants in ClinVar

4 Conditions Cataloged
not specifiedTotal: 56
Neurocardiofaciodigital syndromeTotal: 7
not providedTotal: 5
Syndromic diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003668.4. 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
6
clinvar
 8
missense
1
clinvar
58
clinvar
1
clinvar
 60
nonsense
2
clinvar
1
clinvar
 3
start loss
0
frameshift
3
clinvar
 3
splice donor/acceptor (+/-2bp)
7
clinvar
 7
Total60687081

Highest pathogenic variant AF is 0.0000034415448

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003668.4RefSeqNP_003659.214MANE Select
ENST00000550735.7EnsemblENSP00000449667.214MANE Select
NM_001371479.1RefSeqNP_001358408.115Standard
NM_001371480.1RefSeqNP_001358409.115Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • MAPK signaling pathway - Homo sapiens (human)
  • EGF-Core
  • MAPK6-MAPK4 signaling
  • MAPK Signaling Pathway
  • VEGFA-VEGFR2 Signaling Pathway

Biological Process

  • MAPK cascade
  • activation of MAPK activity
  • regulation of translation
  • signal transduction
  • Ras protein signal transduction

Molecular Function

  • p53 binding
  • protein serine/threonine kinase activity
  • calmodulin-dependent protein kinase activity
  • MAP kinase kinase activity
  • protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000551404
Coding exons
14
Length
54562
Individuals with no LoFs
124643
Homozygous LoFs
0
Heterozygous LoFs
12
Defined
124655
p
0.0000481
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.421442520.5710.00001323108
Missense (PolyPhen)2977.8940.3723995
Synonymous0.8258595.20.8930.00000538852
Loss of Function3.68626.40.2270.00000124332

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000670.000065rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.000100.000099rare
East Asian0.0000580.000056rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000380.000035rare
South Asian0.0000650.000065rare
Other0.000170.00017rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Tumor suppressor serine/threonine-protein kinase involved in mTORC1 signaling and post-transcriptional regulation. Phosphorylates FOXO3, ERK3/MAPK6, ERK4/MAPK4, HSP27/HSPB1, p53/TP53 and RHEB. Acts as a tumor suppressor by mediating Ras- induced senescence and phosphorylating p53/TP53. Involved in post- transcriptional regulation of MYC by mediating phosphorylation of FOXO3: phosphorylation of FOXO3 leads to promote nuclear localization of FOXO3, enabling expression of miR-34b and miR-34c, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent MYC translation. Acts as a negative regulator of mTORC1 signaling by mediating phosphorylation and inhibition of RHEB. Part of the atypical MAPK signaling via its interaction with ERK3/MAPK6 or ERK4/MAPK4: the precise role of the complex formed with ERK3/MAPK6 or ERK4/MAPK4 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPK (ERK3/MAPK6 or ERK4/MAPK4), ERK3/MAPK6 (or ERK4/MAPK4) is phosphorylated and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6 (or ERK4/MAPK4). Mediates phosphorylation of HSP27/HSPB1 in response to PKA/PRKACA stimulation, inducing F-actin rearrangement. {ECO:0000269|PubMed:17254968, ECO:0000269|PubMed:17728103, ECO:0000269|PubMed:19166925, ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:9628874}.;

Recessive Scores

pRec
0.138

Intolerance Scores

LoFtool
0.702
RVIS EVS
-0.63
RVIS percentile EVS
17.03

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.891

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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