CDK5RAP2

Chr 9

CDK5 regulatory subunit associated protein 2

Also known as: C48, Cep215, MCPH3

NCBI Gene: 55755 ENSG00000136861 UniProt: Q96SN8

The protein regulates CDK5 activity and localizes to the centrosome where it functions in centriole engagement and microtubule nucleation. Mutations cause primary microcephaly 3, an autosomal recessive disorder characterized by reduced brain size. The pathogenic mechanism involves dominant-negative effects that disrupt normal centrosome function and microtubule organization.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a regulator of CDK5 (cyclin-dependent kinase 5) activity. The protein encoded by this gene is localized to the centrosome and Golgi complex, interacts with CDK5R1 and pericentrin (PCNT), plays a role in centriole engagement and microtubule nucleation, and has been linked to primary microcephaly and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.66

Clinical Summary— CDK5RAP2

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Gene-Disease Validity (ClinGen)

autosomal recessive primary microcephaly · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 96 VUS of 199 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.000

Z-score 4.41

OE 0.53 (0.42–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.37Z-score

OE missense 1.03 (0.98–1.09)

1005 obs / 972.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.53 (0.42–0.66)

0≤0.351.4

Missense OE?1.03 (0.98–1.09)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 54 / 102.1Missense obs/exp: 1005 / 972.5Syn Z: 0.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCDK5RAP2-related primary microcephalyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6936th %ile

GOF

0.5563th %ile

LOF

0.3356th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

199 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic6

VUS96

Likely Benign43

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	0	0	0	6
Likely Pathogenic	6	0	0	0	6
VUS	0	95	0	1	96
Likely Benign	0	9	20	14	43
Benign	0	0	0	0	0
Conflicting	—				1
Total	12	104	20	15	152

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

View in ClinVar →

1 pathogenic / likely-pathogenic (of 1) ClinVar copy-number / structural variants overlap CDK5RAP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →