CDK5RAP2

Chr 9AR

CDK5 regulatory subunit associated protein 2

Also known as: C48, Cep215, MCPH3

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismARLOEUF 0.661 OMIM phenotype
Clinical SummaryCDK5RAP2
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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.
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ClinVar Variants
36 unique Pathogenic / Likely Pathogenic· 228 VUS of 500 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.66LOEUF
pLI 0.000
Z-score 4.41
OE 0.53 (0.420.66)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
-0.37Z-score
OE missense 1.03 (0.981.09)
1005 obs / 972.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.53 (0.420.66)
00.351.4
Missense OE1.03 (0.981.09)
00.61.4
Synonymous OE0.98
01.21.6
LoF obs/exp: 54 / 102.1Missense obs/exp: 1005 / 972.5Syn Z: 0.35
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongCDK5RAP2-related primary microcephalyLOFAR

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

DN
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

500 submitted variants in ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic12
VUS228
Likely Benign180
Benign5
Conflicting4
24
Pathogenic
12
Likely Pathogenic
228
VUS
180
Likely Benign
5
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
0
3
0
24
Likely Pathogenic
11
1
0
0
12
VUS
3
220
4
1
228
Likely Benign
0
17
71
92
180
Benign
0
1
4
0
5
Conflicting
4
Total352398293453

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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