Is PANK2 p.Ser248= (c.744A>C) pathogenic?

PANK2 p.Ser248= (c.744A>C) is classified Conflicting classifications of pathogenicity in PANK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-08). Ultra-rare (popmax 0.0395%, sas); Associated with pantothenate kinase-associated neurodegeneration.

What condition is associated with PANK2 p.Ser248= (c.744A>C)?

PANK2 p.Ser248= (c.744A>C) is associated with pantothenate kinase-associated neurodegeneration (ClinVar).

How common is PANK2 p.Ser248= (c.744A>C) in the general population?

PANK2 p.Ser248= (c.744A>C) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

PANK2 p.Ser248=

Q: How is Pantothenate kinase-associated neurodegeneration inherited?

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

c.744A>C · rs778370524 · VCV287218

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Conditions

pantothenate kinase-associated neurodegeneration

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.53	GERP -3.8, phastCons 0.83
Overall
CADD	7.522	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0395% South Asian · 36/91,086 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00452% 73/1,614,220 alleles · ultra-rare exomes 68/1,461,862 · genomes 5/152,358 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.01%	10,004
East Asian	0.00223%	44,876
European (non-Finnish)	0.00161%	62,107

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.Ser248=
Coding: c.744A>C
MANE Select: NM_001386393
dbSNP: rs778370524
Type: single nucleotide variant
Location: chr20:3910669 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.99 · 1 PDB
Residue 248: an α-helix

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

For Pantothenate kinase-associated neurodegeneration (Orphanet):

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

Similar variants

PANK2 c.1082+1G>C Likely pathogenic ★★ same condition
PANK2 c.1083-1G>T Pathogenic/Likely pathogenic ★★ same condition
PANK2 c.1207-3C>G Pathogenic/Likely pathogenic ★★ same condition
PANK2 c.299-1G>A Likely pathogenic ★★ same condition
PANK2 c.905+1G>C Pathogenic ★★ same condition
PANK2 c.-21G>T Pathogenic/Likely pathogenic ★★ same condition
PANK2 p.Arg154Gln Pathogenic/Likely pathogenic ★★ same condition
PANK2 p.Arg154Trp Pathogenic/Likely 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-ser248 (accessed [today's date]).

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