Is PANK2 p.Arg247Pro (c.740G>C) pathogenic?

PANK2 p.Arg247Pro (c.740G>C) is classified Pathogenic/Likely pathogenic in PANK2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.3672); Very rare (popmax 0.00667%, amr); Associated with pantothenate kinase-associated neurodegeneration.

What condition is associated with PANK2 p.Arg247Pro (c.740G>C)?

PANK2 p.Arg247Pro (c.740G>C) is associated with pantothenate kinase-associated neurodegeneration (ClinVar).

How common is PANK2 p.Arg247Pro (c.740G>C) in the general population?

PANK2 p.Arg247Pro (c.740G>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PANK2 p.Arg247Pro (c.740G>C)?

AlphaMissense predicts ambiguous (score 0.3672) — an in-silico prediction, not a clinical call.

PANK2 p.Arg247Pro

Q: How is Pantothenate kinase-associated neurodegeneration inherited?

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

c.740G>C · rs754521581 · VCV803594

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

pantothenate kinase-associated neurodegeneration

Computational evidence

Protein change
AlphaMissense	0.3672	ambiguous
REVEL	0.43	indeterminate
SaProt	LLR -9.96	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP -2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 29 kb · p 0.51 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R357P vs ClinVar R247P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000496% 8/1,614,102 alleles · very rare exomes 8/1,461,856 · genomes 0/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
African / African-American	0.00133%	75,026
European (non-Finnish)	0.000254%	393,342

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.Arg247Pro
Coding: c.740G>C
MANE Select: NM_001386393
dbSNP: rs754521581
Type: single nucleotide variant
Location: chr20:3910665 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.99 · 1 PDB
Residue 357 UniProt numbering: a UniProt-annotated variant site (in nbia1); a β-strand

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 p.Arg247Trp Pathogenic ★★ ⚠ same residue
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

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-arg247pro (accessed [today's date]).

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