CDK5

Chr 7AR

cyclin dependent kinase 5

Also known as: LIS7, PSSALRE

NCBI Gene: 1020 ENSG00000164885 UniProt: Q00535 OMIM: 123831

This gene encodes a proline-directed serine/threonine kinase that functions in neuronal migration, synaptic plasticity, and cytoskeletal organization by phosphorylating key proteins involved in these processes. Mutations cause autosomal recessive lissencephaly-7 with cerebellar hypoplasia, a severe brain malformation disorder. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.562) and has high expression in postmitotic central nervous system neurons.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a proline-directed serine/threonine kinase that is a member of the cyclin-dependent kinase family of proteins. Unlike other members of the family, the protein encoded by this gene does not directly control cell cycle regulation. Instead the protein, which is predominantly expressed at high levels in mammalian postmitotic central nervous system neurons, functions in diverse processes such as synaptic plasticity and neuronal migration through phosphorylation of proteins required for cytoskeletal organization, endocytosis and exocytosis, and apoptosis. In humans, an allelic variant of the gene that results in undetectable levels of the protein has been associated with lethal autosomal recessive lissencephaly-7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.561 OMIM phenotype

Clinical Summary— CDK5

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Gene-Disease Validity (ClinGen)

lissencephaly with cerebellar hypoplasia · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 14 VUS of 87 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CDK5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.139

Z-score 2.94

OE 0.27 (0.14–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.07Z-score

OE missense 0.33 (0.27–0.42)

56 obs / 167.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.27 (0.14–0.56)

0≤0.351.4

Missense OE?0.33 (0.27–0.42)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 5 / 18.7Missense obs/exp: 56 / 167.8Syn Z: 0.03

This gene — mechanism propensity

0.6936th %ile

GOF

0.6052th %ile

LOF

0.3647th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

87 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS14

Likely Benign48

Benign11

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	1	12	1	0	14
Likely Benign	0	0	20	28	48
Benign	0	0	10	1	11
Conflicting	—				1
Total	2	13	31	29	76

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

View in ClinVar →

74 pathogenic / likely-pathogenic (of 85) ClinVar copy-number / structural variants overlap CDK5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →