Is PANK2 p.Ser59fs (c.175_182del) pathogenic?

PANK2 p.Ser59fs (c.175182del) is classified Pathogenic/Likely pathogenic in PANK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-01). Ultra-rare (popmax 0.0141%, amr); Associated with pantothenate kinase-associated neurodegeneration.

What condition is associated with PANK2 p.Ser59fs (c.175_182del)?

PANK2 p.Ser59fs (c.175_182del) is associated with pantothenate kinase-associated neurodegeneration, hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (ClinVar).

How common is PANK2 p.Ser59fs (c.175_182del) in the general population?

PANK2 p.Ser59fs (c.175_182del) is ultra-rare (popmax 0.0141%, amr) (gnomAD).

PANK2 p.Ser59fs

Q: How is Pantothenate kinase-associated neurodegeneration inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.175_182del · rs755653150 · VCV504213

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, amr)

Conditions

pantothenate kinase-associated neurodegeneration

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP -0.88, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0141% Admixed American · 7/49,586 alleles

Filtering AF 0.00655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00465%

Overall 0.000461% 7/1,520,068 alleles · ultra-rare exomes 7/1,367,768 · genomes 0/152,300 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PANK2
Protein: p.Ser59fs
Coding: c.175_182del
MANE Select: NM_001386393
dbSNP: rs755653150
Type: Deletion
Location: chr20:3889604 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.99 · 1 PDB
Residue 59: the 'disordered' region

Full PANK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pantothenate kinase-associated neurodegeneration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration

For Pantothenate kinase-associated neurodegeneration (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PANK2 p.Arg371_Glu372delinsGln Pathogenic/Likely pathogenic ★★ same condition
PANK2 p.Gly363_Asn364insTer Pathogenic ★★ same condition
PANK2 p.Gly451fs Pathogenic/Likely pathogenic ★★ same condition
PANK2 p.Ser81fs Pathogenic ★★ same condition
PANK2 p.Tyr252fs Pathogenic/Likely pathogenic ★★ same condition
PANK2 c.906-21_906-19del Likely benign ★★ same condition
PANK2 c.906-99_929del Pathogenic ★ same condition
PANK2 p.Arg330fs Pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pank2-p-ser59fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown