Is PLA2G6 p.Phe262= (c.786C>T) pathogenic?

PLA2G6 p.Phe262= (c.786C>T) is classified Conflicting classifications of pathogenicity in PLA2G6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-27). Ultra-rare (popmax 0.0482%, sas); Associated with neurodegeneration with brain iron accumulation 2A.

What condition is associated with PLA2G6 p.Phe262= (c.786C>T)?

PLA2G6 p.Phe262= (c.786C>T) is associated with neurodegeneration with brain iron accumulation 2A (ClinVar).

How common is PLA2G6 p.Phe262= (c.786C>T) in the general population?

PLA2G6 p.Phe262= (c.786C>T) is ultra-rare (popmax 0.0482%, sas) (gnomAD).

How is Infantile neuroaxonal dystrophy inherited?

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

PLA2G6 p.Phe262=

c.786C>T · rs546742857 · VCV159779

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0482%, sas)

Conditions

neurodegeneration with brain iron accumulation 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.163	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	GERP 1.9, phastCons 1
Overall
CADD	17.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0482% South Asian · 43/89,184 alleles

Filtering AF 0.0367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0328%

Overall 0.00313% 50/1,597,430 alleles · ultra-rare exomes 47/1,445,192 · genomes 3/152,238 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0482%	2,074
Remaining individualsnot grpmax-eligible	0.00809%	12,367
European (non-Finnish)	0.000171%	585,418

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.Phe262=
Coding: c.786C>T
MANE Select: NM_003560
dbSNP: rs546742857
Type: single nucleotide variant
Location: chr22:38139993 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16

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 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
PLA2G6 c.1592-2A>C Pathogenic/Likely pathogenic ★★ same condition
PLA2G6 c.1743-2A>G 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-phe262 (accessed [today's date]).

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