CDKL2

Chr 4

cyclin dependent kinase like 2

Also known as: KKIAMRE, P56

NCBI Gene: 8999 ENSG00000138769 UniProt: Q92772 OMIM: 603442

CDKL2 encodes a serine/threonine protein kinase that localizes primarily to the cytoplasm with some nuclear presence. Mutations cause neurodevelopmental disorders with intellectual disability, seizures, and developmental delays, inherited in an autosomal dominant pattern. The gene shows relatively low constraint to loss-of-function variants, suggesting the associated phenotypes may involve diverse mutational mechanisms.

OMIM ResearchSummary from RefSeq

This gene product is a member of a large family of CDC2-related serine/threonine protein kinases. It accumulates primarily in the cytoplasm, with lower levels in the nucleus. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.43

Clinical Summary— CDKL2

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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

1 unique Pathogenic / Likely Pathogenic· 70 VUS of 84 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.43LOEUF

pLI 0.000

Z-score -0.11

OE 1.02 (0.75–1.43)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.25Z-score

OE missense 1.04 (0.94–1.16)

263 obs / 252.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.02 (0.75–1.43)

0≤0.351.4

Missense OE?1.04 (0.94–1.16)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 25 / 24.4Missense obs/exp: 263 / 252.0Syn Z: -0.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCDKL2-related neurodevelopmental disorderOTHERAD

This gene — mechanism propensity

0.6744th %ile

GOF

0.74top 25%

LOF

0.4331th %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

84 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS70

Likely Benign5

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	1	1
VUS	70	70
Likely Benign	5	5
Benign	0	0
Total	76	76

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap CDKL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →