Is PANK2 p.Asp46Val (c.137A>T) pathogenic?

PANK2 p.Asp46Val (c.137A>T) is classified Benign/Likely benign in PANK2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0965); Rare (popmax 0.214%, nfe); Associated with pantothenate kinase-associated neurodegeneration.

What condition is associated with PANK2 p.Asp46Val (c.137A>T)?

PANK2 p.Asp46Val (c.137A>T) is associated with pantothenate kinase-associated neurodegeneration (ClinVar).

How common is PANK2 p.Asp46Val (c.137A>T) in the general population?

PANK2 p.Asp46Val (c.137A>T) is rare (popmax 0.214%, nfe) (gnomAD).

What do computational predictors say about PANK2 p.Asp46Val (c.137A>T)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

PANK2 p.Asp46Val

Q: How is Pantothenate kinase-associated neurodegeneration inherited?

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

c.137A>T · rs148036492 · VCV425264

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.214%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pantothenate kinase-associated neurodegeneration

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -5.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP -3.7
Overall
CADD	2.76	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.214% European (non-Finnish) · 2,522/1,179,748 alleles

Filtering AF 0.207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.204%

Overall 0.249% 4,016/1,613,306 alleles · rare exomes 3,521/1,460,976 · genomes 495/152,330 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.07%	48
European (non-Finnish)grpmax	0.214%	468
Remaining individualsnot grpmax-eligible	0.152%	657
Admixed American	0.0867%	1,153
African / African-American	0.024%	4,169
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,390
South Asian	0.0022%	45,366

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp46Val
Coding: c.137A>T
MANE Select: NM_001386393 · reported on NM_153638
dbSNP: rs148036492
Type: single nucleotide variant
Location: chr20:3889237 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.99 · 1 PDB
Residue 46: 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-asp46val (accessed [today's date]).

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