PLK4

Chr 4AR

polo like kinase 4

Also known as: MCCRP2, SAK, STK18

NCBI Gene: 10733ENSG00000142731UniProt: O00444

This gene encodes a member of the polo family of serine/threonine protein kinases. The protein localizes to centrioles, complex microtubule-based structures found in centrosomes, and regulates centriole duplication during the cell cycle. Three alternatively spliced transcript variants that encode different protein isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

Primary Disease Associations & Inheritance

Microcephaly and chorioretinopathy, autosomal recessive, 2MIM #616171
AR
0
Active trials
31
Pathogenic / LP
375
ClinVar variants
46
Pubs (1 yr)
0.8
Missense Z
0.57
LOEUF
Clinical Summary— PLK4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 207 VUS of 375 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.57LOEUF
pLI 0.000
Z-score 3.85
OE 0.38 (0.26–0.57)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.80Z-score
OE missense 0.90 (0.83–0.97)
447 obs / 497.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.38 (0.26–0.57)
0≤0.351.4
Missense OE0.90 (0.83–0.97)
0≤0.61.4
Synonymous OE1.13
0≤1.21.6
LoF obs/exp: 17 / 44.8Missense obs/exp: 447 / 497.2Syn Z: -1.31
DNLOF
DN
0.7034th %ile
GOF
0.4481th %ile
LOF
0.4136th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
LOF52% of P/LP variants are LoF

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

375 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic8
VUS207
Likely Benign131
Benign2
Conflicting4
23
Pathogenic
8
Likely Pathogenic
207
VUS
131
Likely Benign
2
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
14
0
23
Likely Pathogenic
7
0
1
0
8
VUS
1
187
17
2
207
Likely Benign
0
2
53
76
131
Benign
0
0
2
0
2
Conflicting
—4
Total171898778375

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

View in ClinVar →

PLK4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PLK4-related microcephaly, growth failure and retinopathy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Role of PLK4 inhibition in cancer therapy.
Banik K et al.·Cancer Metastasis Rev
2025Review
PLK4: a link between centriole biogenesis and cancer.
Maniswami RR et al.·Expert Opin Ther Targets
2018Review
PLK4: a promising target for cancer therapy.
Zhao Y et al.·J Cancer Res Clin Oncol
2019Review
Polo-like kinases and acute leukemia.
Goroshchuk O et al.·Oncogene
2019Review
Polo-like kinase 4 (PLK4) as a therapeutic target in breast cancer.
Parsyan A et al.·Carcinogenesis
2025Review
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients