PNKP

Chr 19AR

polynucleotide kinase 3'-phosphatase

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

NCBI Gene: 11284 ENSG00000039650 UniProt: Q96T60 OMIM: 605610

The protein catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids in response to ionizing radiation or oxidative damage as part of DNA repair. Autosomal recessive mutations cause microcephaly, seizures, and developmental delay, ataxia-oculomotor apraxia 4, and possibly Charcot-Marie-Tooth disease type 2B2. Pathogenicity results from impaired DNA repair mechanisms following cellular damage.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.213 OMIM phenotypes

Clinical Summary— PNKP

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Gene-Disease Validity (ClinGen)

microcephaly, seizures, and developmental delay · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

148 unique Pathogenic / Likely Pathogenic· 479 VUS of 1276 total submissions

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GeneReview available — PNKP

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-1.31Z-score

OE missense 1.21 (1.11–1.31)

383 obs / 317.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.85 (0.61–1.21)

0≤0.351.4

Missense OE?1.21 (1.11–1.31)

0≤0.61.4

Synonymous OE?1.49

0≤1.21.6

LoF obs/exp: 23 / 26.9Missense obs/exp: 383 / 317.4Syn Z: -4.53

ClinVar Variant Classifications

1276 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic76

Likely Pathogenic72

VUS479

Likely Benign525

Benign27

Conflicting80

Pathogenic

Likely Pathogenic

479

VUS

525

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	68	3	5	0	76
Likely Pathogenic	63	6	2	1	72
VUS	11	414	43	11	479
Likely Benign	1	7	283	234	525
Benign	0	0	25	2	27
Conflicting	—				80
Total	143	430	358	248	1,259

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap PNKP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →