Is PLA2G6 p.Pro559fs (c.1670dup) pathogenic?

PLA2G6 p.Pro559fs (c.1670dup) is classified Pathogenic in PLA2G6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-22). No gnomAD frequency available for this variant; Associated with neurodegeneration with brain iron accumulation 2A.

What condition is associated with PLA2G6 p.Pro559fs (c.1670dup)?

PLA2G6 p.Pro559fs (c.1670dup) is associated with neurodegeneration with brain iron accumulation 2A (ClinVar).

How common is PLA2G6 p.Pro559fs (c.1670dup) in the general population?

PLA2G6 p.Pro559fs (c.1670dup) is no gnomAD frequency available for this variant (gnomAD).

How is Infantile neuroaxonal dystrophy inherited?

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

PLA2G6 p.Pro559fs

c.1670dup · rs2517951495 · VCV2745815

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

neurodegeneration with brain iron accumulation 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -13	GERP -4.5

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PLA2G6
Protein: p.Pro559fs
Coding: c.1670dup
MANE Select: NM_003560
dbSNP: rs2517951495
Type: Duplication
Location: chr22:38120830 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16
Residue 559: the pnpla domain

Full PLA2G6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodegeneration with brain iron accumulation 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Infantile neuroaxonal dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PLA2G6 p.Pro559Ser Uncertain significance ★ same residue
PLA2G6 p.Pro559= Likely benign ★ same residue
PLA2G6 p.Cys146fs Pathogenic/Likely pathogenic ★★ same condition
PLA2G6 p.Gly517fs Pathogenic/Likely pathogenic ★★ same condition
PLA2G6 c.209+9dup Likely benign ★★ same condition
PLA2G6 p.Arg285fs Pathogenic ★ same condition
PLA2G6 p.Arg612fs Pathogenic ★ same condition
PLA2G6 p.Asp513Ter 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/pla2g6-p-pro559fs (accessed [today's date]).

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