Is PLA2G6 p.Pro593= (c.1779G>A) pathogenic?

PLA2G6 p.Pro593= (c.1779G>A) is classified Likely benign in PLA2G6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-23). Ultra-rare (popmax 0.0986%, mid); Associated with neurodegeneration with brain iron accumulation 2A.

What condition is associated with PLA2G6 p.Pro593= (c.1779G>A)?

PLA2G6 p.Pro593= (c.1779G>A) is associated with neurodegeneration with brain iron accumulation 2A (ClinVar).

How common is PLA2G6 p.Pro593= (c.1779G>A) in the general population?

PLA2G6 p.Pro593= (c.1779G>A) is ultra-rare (popmax 0.0986%, mid) (gnomAD).

How is Infantile neuroaxonal dystrophy inherited?

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

PLA2G6 p.Pro593=

c.1779G>A · rs746984683 · VCV1573057

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, mid)

Conditions

neurodegeneration with brain iron accumulation 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -3.8
Overall
CADD	0.895	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0986% Middle Eastern · 6/6,084 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00328% 53/1,613,786 alleles · ultra-rare exomes 50/1,461,604 · genomes 3/152,182 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0986%	1,014
Remaining individualsnot grpmax-eligible	0.0176%	5,680
South Asian	0.0154%	6,507
Admixed American	0.00833%	12,001
European (non-Finnish)	0.00136%	73,748
African / African-American	0.00133%	74,922

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: PLA2G6
Protein: p.Pro593=
Coding: c.1779G>A
MANE Select: NM_003560
dbSNP: rs746984683
Type: single nucleotide variant
Location: chr22:38116175 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16
Residue 593: 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.Pro593Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PLA2G6 p.Pro593Gln Likely pathogenic ★ ⚠ same residue
PLA2G6 c.1078-1G>A Likely pathogenic ★★ same condition
PLA2G6 c.1186+1G>A Pathogenic/Likely pathogenic ★★ same condition
PLA2G6 c.1186+1G>T Pathogenic/Likely pathogenic ★★ same condition
PLA2G6 c.1187-1G>A Pathogenic/Likely pathogenic ★★ same condition
PLA2G6 c.1349-2A>G Pathogenic/Likely pathogenic ★★ same condition
PLA2G6 c.1427+1G>A 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/pla2g6-p-pro593 (accessed [today's date]).

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