MAP4K2

Chr 11

mitogen-activated protein kinase kinase kinase kinase 2

Also known as: BL44, GCK, RAB8IP

NCBI Gene: 5871 ENSG00000168067 UniProt: Q12851 OMIM: 603166

MAP4K2 encodes a serine/threonine protein kinase that activates MAP kinase signaling pathways, particularly the stress-activated JNK pathway in response to inflammatory stimuli, and acts as a component of the Hippo pathway regulating cell proliferation and apoptosis. Biallelic mutations cause a severe neurodevelopmental disorder with intellectual disability, seizures, and dysmorphic features, inherited in an autosomal recessive pattern. The gene shows tolerance to loss-of-function variation in the general population.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.000

Z-score 3.41

OE 0.50 (0.37–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.60Z-score

OE missense 0.79 (0.73–0.86)

370 obs / 467.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.37–0.69)

0≤0.351.4

Missense OE?0.79 (0.73–0.86)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 27 / 54.0Missense obs/exp: 370 / 467.6Syn Z: -1.33

Background carrier burden — how many people carry a rare variant somewhere in MAP4K2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 75

980 rare PASS variants

Rare truncating (LoF)

1 in 1,100

163 rare PASS variants

Rare synonymous (reference)

1 in 77

511 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MAP4K2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

Exome coverage (gnomAD): 31 of 32 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 31 of 32 (exon 25 below).? see exons ↓