Is PLA2G6 p.Leu129Pro (c.386T>C) pathogenic?

PLA2G6 p.Leu129Pro (c.386T>C) is classified Conflicting classifications of pathogenicity in PLA2G6 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.9468); Ultra-rare (popmax 0.0548%, afr); Associated with PLA2G6-associated neurodegeneration.

What condition is associated with PLA2G6 p.Leu129Pro (c.386T>C)?

PLA2G6 p.Leu129Pro (c.386T>C) is associated with PLA2G6-associated neurodegeneration, neurodegeneration with brain iron accumulation 2B, autosomal recessive Parkinson disease 14 (ClinVar).

How common is PLA2G6 p.Leu129Pro (c.386T>C) in the general population?

PLA2G6 p.Leu129Pro (c.386T>C) is ultra-rare (popmax 0.0548%, afr) (gnomAD).

What do computational predictors say about PLA2G6 p.Leu129Pro (c.386T>C)?

AlphaMissense predicts likely pathogenic (score 0.9468) — an in-silico prediction, not a clinical call.

PLA2G6 p.Leu129Pro

c.386T>C · rs374746113 · VCV159768

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9468 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0548%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PLA2G6-associated neurodegeneration

Computational evidence

Protein change
AlphaMissense	0.9468	likely pathogenic
REVEL	0.392	indeterminate
SaProt	LLR -14.60	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 57 kb · p 2e-06 · regional, not allelic
Overall
CADD	26.2	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 0.0548% African / African-American · 41/74,876 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0368%

Overall 0.00261% 42/1,611,876 alleles · ultra-rare exomes 16/1,459,730 · genomes 26/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0548%	1,826
Remaining individualsnot grpmax-eligible	0.0016%	62,382

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.Leu129Pro
Coding: c.386T>C
MANE Select: NM_003560
dbSNP: rs374746113
Type: single nucleotide variant
Location: chr22:38145477 (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

PLA2G6-associated neurodegeneration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodegeneration with brain iron accumulation 2B autosomal recessive Parkinson disease 14 neurodegeneration with brain iron accumulation neurodegeneration with brain iron accumulation 2A

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.1427+1G>C Likely pathogenic ★★ same condition
PLA2G6 c.1592-2A>C 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-leu129pro (accessed [today's date]).

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