CDKL5

Chr XXLD

cyclin dependent kinase like 5

Also known as: CFAP247, DEE2, EIEE2, ISSX, STK9

NCBI Gene: 6792 ENSG00000008086 UniProt: O76039 OMIM: 300203

This serine/threonine kinase mediates phosphorylation of MECP2 and may regulate ciliogenesis. Mutations cause developmental and epileptic encephalopathy 2 (including X-linked infantile spasm syndrome and some cases of Rett syndrome) through an X-linked dominant inheritance pattern, predominantly through loss-of-function mechanisms. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as a pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismXLDLOEUF 0.231 OMIM phenotype

VCEP Guidelines: Rett/Angelman-like DisordersPilot

View Specifications ClinGen Panel

Clinical Summary— CDKL5

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Gene-Disease Validity (ClinGen)

CDKL5 disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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ClinVar Variants

115 unique Pathogenic / Likely Pathogenic· 116 VUS of 500 total submissions

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Clinical Trials

8 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CDKL5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.23LOEUF

pLI 0.999

Z-score 4.95

OE 0.09 (0.04–0.23)

Highly constrained

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

Missense Constraint

2.74Z-score

OE missense 0.62 (0.55–0.68)

246 obs / 400.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.09 (0.04–0.23)

0≤0.351.4

Missense OE0.62 (0.55–0.68)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 3 / 34.3Missense obs/exp: 246 / 400.0Syn Z: -0.50

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCDKL5-related epileptic encephalopathy, early infantileLOFmonoallelic_X_heterozygous

0.3793th %ile

GOF

0.3986th %ile

LOF

0.81top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 59% of P/LP variants are LoF · LOEUF 0.23

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

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68

Likely Pathogenic47

VUS116

Likely Benign92

Benign26

Conflicting6

Pathogenic

Likely Pathogenic

116

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	49	6	12	1	68
Likely Pathogenic	19	27	1	0	47
VUS	2	105	8	1	116
Likely Benign	0	11	39	42	92
Benign	0	0	24	2	26
Conflicting	—				6
Total	70	149	84	46	355

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

View in ClinVar →

Protein Context — Lollipop Plot

CDKL5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — CDKL5

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

CDKL5CDKL5 Deficiency DisorderCDD

International CDKL5 Clinical Research Network

RECRUITING

NCT05558371University of Colorado, DenverStarted 2021-02-15

No intervention.

Dravet Syndrome

Longitudinal Study of Phenotypic and Developmental Severity in Patients With Dravet Syndrome With SCN1A Gene Mutation

RECRUITING

NCT07251673Assistance Publique - Hôpitaux de ParisStarted 2025-09-15

Dravet Syndrome

A Clinical Study to Evaluate the Safety and Efficacy of ETX101 in Infants and Children With SCN1A-Positive Dravet Syndrome

RECRUITING

NCT05419492Phase PHASE1, PHASE2Encoded TherapeuticsStarted 2024-05-14

ETX101

Dravet SyndromeEpilepsy

Neurodevelopmental Impact of Epilepsy on Autonomic Function in Dravet Syndrome

ACTIVE NOT RECRUITING

NCT05472389Phase NAHospices Civils de LyonStarted 2022-10-14

Video-electroencephalographyBlood Samples

Dravet Syndrome

A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome (Australia Only)

ACTIVE NOT RECRUITING

NCT06112275Phase PHASE1, PHASE2Encoded TherapeuticsStarted 2024-02-28

ETX101

Dravet Syndrome

A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome

ACTIVE NOT RECRUITING

NCT06283212Phase PHASE1, PHASE2Encoded TherapeuticsStarted 2024-05-09

ETX101

EpilepsyDravet SyndromeDrug Resistant Epilepsy

A PET-MRI Study of Serotoninergic Brainstem Pathway in Patients With Dravet Syndrome

RECRUITING

NCT07013331Phase NAHospices Civils de LyonStarted 2026-05-04