MAP4K2

protein-coding

mitogen-activated protein kinase kinase kinase kinase 2, the group of Mitogen-activated protein kinase kinase kinase kinases

Gene summary

The protein encoded by this gene is a member of the serine/threonine protein kinase family. Although this kinase is found in many tissues, its expression in lymphoid follicles is restricted to the cells of germinal centre, where it may participate in B-cell differentiation. This kinase can be activated by TNF-alpha, and has been shown to specifically activate MAP kinases. This kinase is also found to interact with TNF receptor-associated factor 2 (TRAF2), which is involved in the activation of MAP3K1/MEKK1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

Previous symbols:

RAB8IP

MANE transcript

NM_004579.5

Inheritance

—

ClinVar variants

U:139B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr11:64,784,918-64,803,241

External References & Databases

Ensembl (ENSG00000168067)

Transcript & Mutation Effects

hg38 • Region Span ~18.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAP4K2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 123

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004579.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	2 clinvar	2 clinvar	7
missense			125 clinvar	1 clinvar	2 clinvar	128
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	0	0	139	3	4	146

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004579.5	RefSeq	NP_004570.2	32	MANE Select
ENST00000294066.7	Ensembl	ENSP00000294066.2	32	MANE Select
NM_001307990.2	RefSeq	NP_001294919.1	32	Standard
ENST00000377350.7	Ensembl	ENSP00000366567.3	32	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MAPK signaling pathway - Homo sapiens (human)
EGF-Core
TNF alpha Signaling Pathway
MAPK Signaling Pathway
Angiopoietin Like Protein 8 Regulatory Pathway

Biological Process

activation of MAPKKK activity
protein phosphorylation
vesicle targeting
immune response
JNK cascade

Molecular Function

protein serine/threonine kinase activity
protein binding
ATP binding
MAP kinase kinase kinase kinase activity
mitogen-activated protein kinase kinase kinase binding

Cellular Component

Golgi membrane
cytoplasm
basolateral plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000294066
Coding exons: 32
Length: 14424
Individuals with no LoFs: 125652
Homozygous LoFs: 0
Heterozygous LoFs: 96
Defined: 125748
p: 0.000382

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.60	370	468	0.791	0.0000271	5223
Missense (PolyPhen)		58	102.64	0.56507		1241
Synonymous	-1.33	225	201	1.12	0.0000124	1649
Loss of Function	3.41	27	54.0	0.500	0.00000267	590

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00070	0.00069	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00055	0.00055	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00020	0.00020	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extent of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion. {ECO:0000269|PubMed:11784851, ECO:0000269|PubMed:15456887, ECO:0000269|PubMed:17584736, ECO:0000269|PubMed:7477268, ECO:0000269|PubMed:7515885, ECO:0000269|PubMed:9712898}.;

Recessive Scores

pRec: 0.742

Intolerance Scores

LoFtool: 0.744
RVIS EVS: -1.04
RVIS percentile EVS: 7.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium