Is PLA2G6 p.Glu751= (c.2253G>A) pathogenic?

PLA2G6 p.Glu751= (c.2253G>A) is classified Likely benign in PLA2G6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-23). Very rare (popmax 0.00243%, eas); Associated with neurodegeneration with brain iron accumulation 2A.

What condition is associated with PLA2G6 p.Glu751= (c.2253G>A)?

PLA2G6 p.Glu751= (c.2253G>A) is associated with neurodegeneration with brain iron accumulation 2A (ClinVar).

How common is PLA2G6 p.Glu751= (c.2253G>A) in the general population?

PLA2G6 p.Glu751= (c.2253G>A) is very rare (popmax 0.00243%, eas) (gnomAD).

How is Infantile neuroaxonal dystrophy inherited?

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

PLA2G6 p.Glu751=

c.2253G>A · rs544263173 · VCV2980944

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00243%, eas)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Overall
CADD	9.368	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00243% East Asian · 1/41,118 alleles

Overall 6.43e-05% 1/1,556,180 alleles · very rare exomes 0/1,403,926 · genomes 1/152,254 · joint denominator

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.Glu751=
Coding: c.2253G>A
MANE Select: NM_003560
dbSNP: rs544263173
Type: single nucleotide variant
Location: chr22:38112527 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16
Residue 751: the 'calmodulin-binding (iq motif)' region

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.Glu751Ter Pathogenic ★★ same residue
PLA2G6 p.Glu751Lys Conflicting classifications of pathogenicity ★ 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-glu751 (accessed [today's date]).

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