CDK5RAP2

Chr 9

CDK5 regulatory subunit associated protein 2

Also known as: C48, Cep215, MCPH3

NCBI Gene: 55755ENSG00000136861UniProt: Q96SN8

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]

Primary Disease Associations & Inheritance

UniProtMicrocephaly 3, primary, autosomal recessive
551
ClinVar variants
58
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— CDK5RAP2
🧬
Gene-Disease Validity (ClinGen)
autosomal recessive primary microcephaly · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 270 VUS of 551 total submissions
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?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.
0.66LOEUF
pLI 0.000
Z-score 4.41
OE 0.53 (0.42–0.66)
Tolerant

Typical tolerance to LoF variation

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.
-0.37Z-score
OE missense 1.03 (0.98–1.09)
1005 obs / 972.5 exp
Tolerant

Tolerant to missense variation

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.0.53 (0.42–0.66)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.03 (0.98–1.09)
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.0.98
0≤1.21.6
LoF obs/exp: 54 / 102.1Missense obs/exp: 1005 / 972.5Syn Z: 0.35

ClinVar Variant Classifications

551 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic17
VUS270
Likely Benign181
Benign14
Conflicting28
41
Pathogenic
17
Likely Pathogenic
270
VUS
181
Likely Benign
14
Benign
28
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
1
24
0
41
Likely Pathogenic
9
1
7
0
17
VUS
2
257
6
5
270
Likely Benign
0
21
63
97
181
Benign
0
1
12
1
14
Conflicting
—28
Total27281112103551

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

View in ClinVar →

Protein Context — Lollipop Plot

CDK5RAP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CDK5RAP2-related primary microcephaly

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A Rare Cause of Primary Microcephaly: 4 New Variants in CDK5RAP2 Gene and Review of the Literature.
Erdogan M et al.·Am J Med Genet A
2025Review
CDK5RAP2 is a Wnt target gene and promotes stemness and progression of oral squamous cell carcinoma.
Shen Y et al.·Cell Death Dis
2023
CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway.
Wang X et al.·Cell Death Dis
2021
MORC2 regulates RBM39-mediated CDK5RAP2 alternative splicing to promote EMT and metastasis in colon cancer.
He Y et al.·Cell Death Dis
2024
A novel missense variant in CDK5RAP2 associated with non-obstructive azoospermia.
Rahimian M et al.·Taiwan J Obstet Gynecol
2023
CDK5RAP2 gene and tau pathophysiology in late-onset sporadic Alzheimer's disease.
Miron J et al.·Alzheimers Dement
2018
Proteome changes in autosomal recessive primary microcephaly.
Zaqout S et al.·Ann Hum Genet
2023
Identification of CDK5RAP2 as a causative gene of focal epilepsy without microcephaly.
Li X et al.·Seizure
2025
Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation.
Issa L et al.·Orphanet J Rare Dis
2013Cohort
Species-Specific Expression of Full-Length and Alternatively Spliced Variant Forms of CDK5RAP2.
Park JS et al.·PLoS One
2015
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools