PKMYT1

Chr 16

protein kinase, membrane associated tyrosine/threonine 1

Also known as: MYT1, PPP1R126

NCBI Gene: 9088 ENSG00000127564 UniProt: Q99640 OMIM: 602474

The protein encoded by this gene is a membrane-associated serine/threonine kinase that negatively regulates cell cycle progression by phosphorylating and inactivating cyclin-dependent kinase 1, thereby controlling the transition from G2 phase to mitosis. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, typically presenting in early infancy with severe seizures and developmental delays. The gene shows moderate tolerance to loss-of-function variants, and the associated disorder primarily affects the central nervous system with prominent neurodevelopmental features.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the serine/threonine protein kinase family. The encoded protein is a membrane-associated kinase that negatively regulates the G2/M transition of the cell cycle by phosphorylating and inactivating cyclin-dependent kinase 1. The activity of the encoded protein is regulated by polo-like kinase 1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.52

Clinical Summary— PKMYT1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

104 VUS of 125 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.219

Z-score 3.13

OE 0.25 (0.13–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.07Z-score

OE missense 0.99 (0.90–1.09)

286 obs / 289.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.13–0.52)

0≤0.351.4

Missense OE?0.99 (0.90–1.09)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 5 / 20.2Missense obs/exp: 286 / 289.5Syn Z: -0.62

This gene — mechanism propensity

0.6551th %ile

GOF

0.6737th %ile

LOF

0.4037th %ile

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

GOFprediction above median

DNprediction 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

125 submitted variants in ClinVar

ClinVar

Classification Summary

VUS104

Likely Benign2

Benign1

104

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	104	0	104
Likely Benign	2	0	2
Benign	0	1	1
Total	106	1	107

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap PKMYT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →