PNKP

Chr 19AR

polynucleotide kinase 3'-phosphatase

Also known as: AOA4, CMT2B2, EIEE10, MCSZ, PNK

NCBI Gene: 11284ENSG00000039650UniProt: Q96T60

This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

Primary Disease Associations & Inheritance

?Charcot-Marie-Tooth disease, type 2B2MIM #605589
AR
Ataxia-oculomotor apraxia 4MIM #616267
AR
Microcephaly, seizures, and developmental delayMIM #613402
AR
582
ClinVar variants
79
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PNKP
🧬
Gene-Disease Validity (ClinGen)
microcephaly, seizures, and developmental delay · 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
79 Pathogenic / Likely Pathogenic· 206 VUS of 582 total submissions

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.
1.21LOEUF
pLI 0.000
Z-score 0.70
OE 0.85 (0.61–1.21)
Tolerant

Highly tolerant — LoF variants common in population

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.
-1.31Z-score
OE missense 1.21 (1.11–1.31)
383 obs / 317.4 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.0.85 (0.61–1.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.21 (1.11–1.31)
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.1.49
0≤1.21.6
LoF obs/exp: 23 / 26.9Missense obs/exp: 383 / 317.4Syn Z: -4.53

ClinVar Variant Classifications

582 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic32
VUS206
Likely Benign285
Benign8
Conflicting4
47
Pathogenic
32
Likely Pathogenic
206
VUS
285
Likely Benign
8
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
34
0
13
0
47
Likely Pathogenic
23
3
5
1
32
VUS
6
173
25
2
206
Likely Benign
0
2
163
120
285
Benign
0
0
8
0
8
Conflicting
—4
Total63178214123582

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

View in ClinVar →

Protein Context — Lollipop Plot

PNKP · protein map & ClinVar variants

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

Gene2Phenotype Curations

PNKP-related ataxia-oculomotor apraxia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Charcot-Marie-Tooth disease, type 2B2

MIM #605589

Molecular basis of disorder known

Autosomal recessive

Ataxia-oculomotor apraxia 4

MIM #616267

Molecular basis of disorder known

Autosomal recessive

Microcephaly, seizures, and developmental delay

MIM #613402

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PNKP
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine.
Gohil D et al.·Int J Mol Sci
2023Review
Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease.
Dumitrache LC et al.·Mech Ageing Dev
2017Review
PNKP targeting engages the autophagic machinery through STING and STAT3 to potentiate ferroptosis and chemotherapy in TNBC.
Maimon A et al.·Redox Biol
2025
Fructose-2,6-bisphosphate restores DNA repair activity of PNKP and ameliorates neurodegenerative symptoms in Huntington's disease.
Chakraborty A et al.·Proc Natl Acad Sci U S A
2024
Prenatal phenotype of PNKP-related microcephaly, seizures, and developmental delay: A case report and literature review.
Xie JL et al.·Medicine (Baltimore)
2025Review
Gastric Adenocarcinoma with Enteroblastic Differentiation.
Ferenczi Á et al.·Pathobiology
2025Review
Microcephalic primordial dwarfism in an Emirati patient with PNKP mutation.
Nair P et al.·Am J Med Genet A
2016Review
Clinical and Genetic Characterization of Brazilian Patients with Ataxia and Oculomotor Apraxia.
da Costa SCG et al.·Mov Disord
2022Cohort
Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain.
Neuser S et al.·Eur J Hum Genet
2022Case report
Whole-exome sequencing identifies new pathogenic germline variants in patients with colorectal polyposis.
Dos Santos W et al.·World J Gastroenterol
2025Cohort
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