PLK3

Chr 1

polo like kinase 3

Also known as: CNK, FNK, PLK-3, PRK

NCBI Gene: 1263 ENSG00000173846 UniProt: Q9H4B4

PLK3 encodes a serine/threonine kinase that regulates cell cycle progression, DNA damage response, and cellular stress responses by phosphorylating multiple target proteins including p53, CDC25A, and CHEK2. The gene is highly constrained against loss-of-function variants (pLI near 1.0), indicating that haploinsufficiency is likely not tolerated in humans. Pathogenic variants in PLK3 have not yet been established as a cause of human disease, despite the protein's critical cellular functions.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the highly conserved polo-like kinase family of serine/threonine kinases. Members of this family are characterized by an amino-terminal kinase domain and a carboxy-terminal bipartite polo box domain that functions as a substrate-binding motif and a cellular localization signal. Polo-like kinases are important regulators of cell cycle progression. This gene has also been implicated in stress responses and double-strand break repair. In human cell lines, this protein is reported to associate with centrosomes in a microtubule-dependent manner, and during mitosis, the protein becomes localized to the mitotic apparatus. Expression of a kinase-defective mutant results in abnormal cell morphology caused by changes in microtubule dynamics and mitotic arrest followed by apoptosis. [provided by RefSeq, Sep 2015]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.71

Clinical Summary— PLK3

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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

91 VUS of 123 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?

0.71LOEUF

pLI 0.000

Z-score 2.83

OE 0.46 (0.31–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.24Z-score

OE missense 0.82 (0.75–0.90)

318 obs / 386.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.31–0.71)

0≤0.351.4

Missense OE?0.82 (0.75–0.90)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 15 / 32.4Missense obs/exp: 318 / 386.5Syn Z: -0.12

This gene — mechanism propensity

0.6938th %ile

GOF

0.6345th %ile

LOF

0.3261th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-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

GOFprediction above median

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.

ClinVar Variant Classifications

123 submitted variants in ClinVar

ClinVar

Classification Summary

VUS91

Likely Benign4

Benign7

VUS

Likely Benign

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	91	0	0	91
Likely Benign	3	0	1	4
Benign	0	1	6	7
Total	94	1	7	102

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap PLK3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →