Is PANK2 p.Pro91Arg (c.272C>G) pathogenic?

PANK2 p.Pro91Arg (c.272C>G) is classified Uncertain significance in PANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-21). AlphaMissense: likely benign (0.0626); Very rare (popmax 0.0027%, afr); Associated with pantothenate kinase-associated neurodegeneration.

What condition is associated with PANK2 p.Pro91Arg (c.272C>G)?

PANK2 p.Pro91Arg (c.272C>G) is associated with pantothenate kinase-associated neurodegeneration (ClinVar).

How common is PANK2 p.Pro91Arg (c.272C>G) in the general population?

PANK2 p.Pro91Arg (c.272C>G) is very rare (popmax 0.0027%, afr) (gnomAD).

What do computational predictors say about PANK2 p.Pro91Arg (c.272C>G)?

AlphaMissense predicts likely benign (score 0.0626) — an in-silico prediction, not a clinical call.

PANK2 p.Pro91Arg

Q: How is Pantothenate kinase-associated neurodegeneration inherited?

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

c.272C>G · rs757651957 · VCV1004958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0626 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0027%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pantothenate kinase-associated neurodegeneration

Computational evidence

Protein change
AlphaMissense	0.0626	likely benign
REVEL	0.354	indeterminate
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -3.5
Overall
CADD	8.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0027% African / African-American · 2/74,146 alleles

Filtering AF 0.000448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000264%

Overall 0.000825% 13/1,575,270 alleles · very rare exomes 11/1,423,012 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0027%	37,073
Admixed American	0.00188%	53,188
Remaining individualsnot grpmax-eligible	0.00164%	61,028
European (non-Finnish)	0.000775%	129,090

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.Pro91Arg
Coding: c.272C>G
MANE Select: NM_001386393 · reported on NM_153638
dbSNP: rs757651957
Type: single nucleotide variant
Location: chr20:3889372 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.99 · 1 PDB
Residue 91: 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

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-pro91arg (accessed [today's date]).

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