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…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.43

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in CDKL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 99

709 rare PASS variants

Rare truncating (LoF)

1 in 950

152 rare PASS variants

Rare synonymous (reference)

1 in 250

232 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CDKL2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 1,100
South Asian	~43k	1 in 74	1 in 1,100
Remaining (unassigned)	~30k	1 in 69	1 in 990
European (Finnish)	~27k	1 in 670	1 in 410
Admixed American	~22k	1 in 82	1 in 970
African / African American	~21k	1 in 89	1 in 870
East Asian	~20k	1 in 80	1 in 170
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 160	1 in 580

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 12 coding exons well covered in gnomAD exomes; exons 8, 10 marginal. Genomes: all 12.? see exons ↓