Is PANK2 p.Pro256Ala (c.766C>G) pathogenic?

PANK2 p.Pro256Ala (c.766C>G) is classified Uncertain significance in PANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely benign (0.1674); Very rare (popmax 0.00333%, amr); Associated with pantothenate kinase-associated neurodegeneration.

What condition is associated with PANK2 p.Pro256Ala (c.766C>G)?

PANK2 p.Pro256Ala (c.766C>G) is associated with pantothenate kinase-associated neurodegeneration (ClinVar).

How common is PANK2 p.Pro256Ala (c.766C>G) in the general population?

PANK2 p.Pro256Ala (c.766C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PANK2 p.Pro256Ala (c.766C>G)?

AlphaMissense predicts likely benign (score 0.1674) — an in-silico prediction, not a clinical call.

PANK2 p.Pro256Ala

Q: How is Pantothenate kinase-associated neurodegeneration inherited?

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

c.766C>G · rs777624606 · VCV1382752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pantothenate kinase-associated neurodegeneration

Computational evidence

Protein change
AlphaMissense	0.1674	likely benign
REVEL	0.602	indeterminate
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP -1.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 29 kb · p 0.51 · regional, not allelic
Overall
CADD	21.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P366A vs ClinVar P256A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,614,108 alleles · very rare exomes 4/1,461,862 · genomes 0/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
European (non-Finnish)	0.000169%	590,009

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.Pro256Ala
Coding: c.766C>G
MANE Select: NM_001386393
dbSNP: rs777624606
Type: single nucleotide variant
Location: chr20:3910691 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.99 · 1 PDB

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.Pro256Thr Likely pathogenic ★ same residue
PANK2 p.Pro256fs Pathogenic ★ same residue
PANK2 p.Pro256Leu Uncertain significance ★ ⚠ 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

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-pro256ala (accessed [today's date]).

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