MAP3K1

Chr 5AD

mitogen-activated protein kinase kinase kinase 1

Also known as: MAPKKK1, MEKK, MEKK 1, MEKK1, SRXY6

NCBI Gene: 4214 ENSG00000095015 UniProt: Q13233 OMIM: 600982

MAP3K1 encodes a protein kinase that activates ERK and JNK signaling pathways and is a central regulator of NF-kappa-B signaling through phosphorylation of downstream kinases. Mutations cause 46,XY sex reversal, a disorder of sex development where individuals with XY chromosomes develop female external genitalia. This gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variation (pLI >0.99).

OMIM ResearchSummary from OMIM, UniProt

The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. [provided by RefSeq, Mar 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.211 OMIM phenotype

Clinical Summary— MAP3K1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 1.000

Z-score 6.44

OE 0.11 (0.06–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.67Z-score

OE missense 0.83 (0.77–0.88)

609 obs / 737.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.21)

0≤0.351.4

Missense OE?0.83 (0.77–0.88)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 7 / 61.5Missense obs/exp: 609 / 737.0Syn Z: -1.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateMAP3K1-related breast cancer, susceptibility toOTHERAD

definitiveMAP3K1-related 46XY sex reversalLOFAD

This gene — mechanism propensity

0.3594th %ile

GOF

0.4481th %ile

LOF

0.77top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.21

GOF1 literature citation

Literature Evidence

GOFNone of these mutations resulted in diminished or unstable MAP3K1 proteins, in keeping with the observation that knockout of this gene in mouse embryos does not disrupt and, therefore, is not necessary for testis development (44). Rather, these mutations have gain-of-function effects, causing increa1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References