PANK2

Chr 20AR

pantothenate kinase 2

Also known as: C20orf48, HARP, HSS, NBIA1, PKAN

NCBI Gene: 80025 ENSG00000125779 UniProt: Q9BZ23 OMIM: 606157

The protein catalyzes the first committed step in coenzyme A biosynthesis within mitochondria and is subject to feedback inhibition by acyl CoA species. Mutations cause pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1, which is inherited in an autosomal recessive pattern. The pathogenesis involves disrupted coenzyme A metabolism leading to mitochondrial dysfunction and characteristic brain iron accumulation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein belonging to the pantothenate kinase family and is the only member of that family to be expressed in mitochondria. Pantothenate kinase is a key regulatory enzyme in the biosynthesis of coenzyme A (CoA) in bacteria and mammalian cells. It catalyzes the first committed step in the universal biosynthetic pathway leading to CoA and is itself subject to regulation through feedback inhibition by acyl CoA species. Mutations in this gene are associated with HARP syndrome and pantothenate kinase-associated neurodegeneration (PKAN), formerly Hallervorden-Spatz syndrome. Alternative splicing, involving the use of alternate first exons, results in multiple transcripts encoding different isoforms. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.971 OMIM phenotype

Clinical Summary— PANK2

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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

147 unique Pathogenic / Likely Pathogenic· 245 VUS of 813 total submissions

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GeneReview available — PANK2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.97LOEUF

pLI 0.000

Z-score 1.68

OE 0.61 (0.40–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.18Z-score

OE missense 0.97 (0.88–1.07)

298 obs / 306.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.40–0.97)

0≤0.351.4

Missense OE?0.97 (0.88–1.07)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 13 / 21.4Missense obs/exp: 298 / 306.8Syn Z: -2.36

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePANK2-related HARP syndromeLOFAR

This gene — mechanism propensity

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

0.6744th %ile

GOF

0.5071th %ile

LOF

0.4431th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

813 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic84

Likely Pathogenic63

VUS245

Likely Benign330

Benign28

Conflicting49

Pathogenic

Likely Pathogenic

245

VUS

330

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	56	18	10	0	84
Likely Pathogenic	26	35	2	0	63
VUS	7	222	14	2	245
Likely Benign	0	10	98	222	330
Benign	0	1	26	1	28
Conflicting	—				49
Total	89	286	150	225	799

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap PANK2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →