MKNK1

Chr 1

MAPK interacting serine/threonine kinase 1

Also known as: MNK1

NCBI Gene: 8569 ENSG00000079277 UniProt: Q9BUB5

This protein is a serine/threonine kinase that phosphorylates eIF4E to regulate mRNA translation and responds to environmental stress and cytokines. Mutations cause autosomal recessive intellectual disability with seizures and microcephaly. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely pathogenic.

ResearchSummary from RefSeq, UniProt

This gene encodes a Ser/Thr protein kinase that interacts with, and is activated by ERK1 and p38 mitogen-activated protein kinases, and thus may play a role in the response to environmental stress and cytokines. This kinase may also regulate transcription by phosphorylating eIF4E via interaction with the C-terminal region of eIF4G. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Jan 2012]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.03

Clinical Summary— MKNK1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

49 VUS of 75 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.03LOEUF

pLI 0.000

Z-score 1.43

OE 0.70 (0.48–1.03)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.44Z-score

OE missense 0.75 (0.67–0.84)

197 obs / 262.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.48–1.03)

0≤0.351.4

Missense OE?0.75 (0.67–0.84)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 18 / 25.9Missense obs/exp: 197 / 262.6Syn Z: 0.15

This gene — mechanism propensity

0.7035th %ile

GOF

0.6833th %ile

LOF

0.3647th %ile

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

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

75 submitted variants in ClinVar

ClinVar

Classification Summary

VUS49

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	47	2	0	49
Likely Benign	2	1	1	4
Benign	0	0	0	0
Total	49	3	1	53

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

6 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap MKNK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →