CDK5R1

Chr 17

cyclin dependent kinase 5 regulatory subunit 1

Also known as: CDK5P35, CDK5R, NCK5A, p23, p25, p35, p35nck5a

NCBI Gene: 8851 ENSG00000176749 UniProt: Q15078 OMIM: 603460

The CDK5R1 gene encodes p35, a neuron-specific activator of cyclin-dependent kinase 5 that is essential for neurite outgrowth, cortical lamination, and dendritic spine morphogenesis during central nervous system development. Mutations in CDK5R1 cause lissencephaly and cortical dysplasia-cryptogenic epilepsy syndrome, inherited in an autosomal recessive pattern. This gene is highly constrained against loss-of-function mutations, reflecting its critical role in neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene (p35) is a neuron-specific activator of cyclin-dependent kinase 5 (CDK5); the activation of CDK5 is required for proper development of the central nervous system. The p35 form of this protein is proteolytically cleaved by calpain, generating a p25 form. The cleavage of p35 into p25 results in relocalization of the protein from the cell periphery to nuclear and perinuclear regions. P25 deregulates CDK5 activity by prolonging its activation and changing its cellular location. The p25 form accumulates in the brain neurons of patients with Alzheimer's disease. This accumulation correlates with an increase in CDK5 kinase activity, and may lead to aberrantly phosphorylated forms of the microtubule-associated protein tau, which contributes to Alzheimer's disease. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.38

Clinical Summary— CDK5R1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

17 VUS of 25 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.38LOEUF

pLI 0.915

Z-score 2.61

OE 0.00 (0.00–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.91Z-score

OE missense 0.61 (0.52–0.71)

115 obs / 189.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.38)

0≤0.351.4

Missense OE?0.61 (0.52–0.71)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 0 / 7.9Missense obs/exp: 115 / 189.0Syn Z: -0.63

This gene — mechanism propensity

0.3495th %ile

GOF

0.4283th %ile

LOF

0.79top 5%

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

LOFprediction above median · LOEUF 0.38

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

25 submitted variants in ClinVar

ClinVar

Classification Summary

VUS17

Benign4

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	17	0	0	17
Likely Benign	0	0	0	0
Benign	0	1	3	4
Total	17	1	3	21

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap CDK5R1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →