Is PLA2G6 p.Ser504Leu (c.1511C>T) pathogenic?

PLA2G6 p.Ser504Leu (c.1511C>T) is classified Pathogenic/Likely pathogenic in PLA2G6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-27). AlphaMissense: likely benign (0.1757); Very rare (popmax 0.00391%, amr); Associated with neurodegeneration with brain iron accumulation 2A.

What condition is associated with PLA2G6 p.Ser504Leu (c.1511C>T)?

PLA2G6 p.Ser504Leu (c.1511C>T) is associated with neurodegeneration with brain iron accumulation 2A, autosomal recessive Parkinson disease 14, neurodegeneration with brain iron accumulation (ClinVar).

How common is PLA2G6 p.Ser504Leu (c.1511C>T) in the general population?

PLA2G6 p.Ser504Leu (c.1511C>T) is very rare (popmax 0.00391%, amr) (gnomAD).

How is Infantile neuroaxonal dystrophy inherited?

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

What do computational predictors say about PLA2G6 p.Ser504Leu (c.1511C>T)?

AlphaMissense predicts likely benign (score 0.1757) — an in-silico prediction, not a clinical call.

PLA2G6 p.Ser504Leu

c.1511C>T · rs2087622708 · VCV1722386

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1757 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00391%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodegeneration with brain iron accumulation 2A

Computational evidence

Protein change
AlphaMissense	0.1757	likely benign ⚠ discordant with ClinVar
REVEL	0.313	indeterminate
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 57 kb · p 2e-06 · regional, not allelic
Overall
CADD	27.3	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 0.00391% Admixed American · 2/51,132 alleles

Filtering AF 0.000649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000243%

Overall 0.000387% 6/1,551,720 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00391%	25,566
East Asian	0.00243%	41,074
European (non-Finnish)	0.000261%	382,585

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.Ser504Leu
Coding: c.1511C>T
MANE Select: NM_003560
dbSNP: rs2087622708
Type: single nucleotide variant
Location: chr22:38123175 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16
Residue 504: 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

Also linked: autosomal recessive Parkinson disease 14 neurodegeneration with brain iron accumulation

For Infantile neuroaxonal dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PLA2G6 p.Ser504= Uncertain significance ★★ 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
PLA2G6 c.1427+1G>C 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-ser504leu (accessed [today's date]).

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