CDKL5

Chr XXLD

cyclin dependent kinase like 5

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

NCBI Gene: 6792ENSG00000008086UniProt: O76039

This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 2MIM #300672
XLD
546
ClinVar variants
212
Pathogenic / LP
1.00
pLI score· haploinsufficient
8
Active trials
Clinical Summary— CDKL5
🧬
Gene-Disease Validity (ClinGen)
CDKL5 disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
212 Pathogenic / Likely Pathogenic· 185 VUS of 546 total submissions
💊
Clinical Trials
8 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.04–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.62 (0.55–0.68)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 3 / 34.3Missense obs/exp: 246 / 400.0Syn Z: -0.50

ClinVar Variant Classifications

546 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic126
Likely Pathogenic86
VUS185
Likely Benign134
Benign10
Conflicting5
126
Pathogenic
86
Likely Pathogenic
185
VUS
134
Likely Benign
10
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
58
16
51
1
126
Likely Pathogenic
32
42
12
0
86
VUS
4
150
27
4
185
Likely Benign
1
12
62
59
134
Benign
0
5
5
0
10
Conflicting
—5
Total9522515764546

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.

Gene2Phenotype Curations

CDKL5-related epileptic encephalopathy, early infantile

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 2

MIM #300672

Molecular basis of disorder known

X-linked dominant
📖
GeneReview available — CDKL5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
X-Linked Epilepsies: A Narrative Review.
Bernardo P et al.·Int J Mol Sci
2024Review
CDKL5 deficiency disorder: clinical features, diagnosis, and management.
Leonard H et al.·Lancet Neurol
2022Review
De novo genic mutations among a Chinese autism spectrum disorder cohort.
Wang T et al.·Nat Commun
2016Cohort
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.
Lindy AS et al.·Epilepsia
2018Cohort
The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
Burgess R et al.·Ann Neurol
2019
Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods.
McKnight D et al.·Hum Mutat
2022
Genetic determinants of global developmental delay and intellectual disability in Ukrainian children.
Shchubelka K et al.·J Neurodev Disord
2024
Preclinical studies of gene replacement therapy for CDKL5 deficiency disorder.
Voronin G et al.·Mol Ther
2024
Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox-Gastaut Syndrome.
Lattanzi S et al.·CNS Drugs
2021Review
Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial.
Knight EMP et al.·Lancet Neurol
2022Clinical trial
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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 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

ACTIVE NOT RECRUITING
NCT06283212Phase PHASE1, PHASE2Encoded TherapeuticsStarted 2024-05-09
ETX101
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 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
EpilepsyDravet SyndromeDrug Resistant Epilepsy

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

NOT YET RECRUITING
NCT07013331Phase NAHospices Civils de LyonStarted 2026-04-01
[18F]MPPF PET-MRI
Dravet Syndrome

EXploring novEl Molecular Determinants of DRAvet Syndrome Phenotype Heterogeneity

ENROLLING BY INVITATION
NCT06371794Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2023-07-06
skin punch biopsy

External Resources

Links to major genomics databases and tools