Is PLA2G6 p.Arg306Gln (c.917G>A) pathogenic?

PLA2G6 p.Arg306Gln (c.917G>A) is classified Uncertain significance in PLA2G6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.076); Ultra-rare (popmax 0.0169%, amr); Associated with Inborn genetic diseases.

What condition is associated with PLA2G6 p.Arg306Gln (c.917G>A)?

PLA2G6 p.Arg306Gln (c.917G>A) is associated with Inborn genetic diseases, neurodegeneration with brain iron accumulation 2A (ClinVar).

How common is PLA2G6 p.Arg306Gln (c.917G>A) in the general population?

PLA2G6 p.Arg306Gln (c.917G>A) is ultra-rare (popmax 0.0169%, amr) (gnomAD).

What do computational predictors say about PLA2G6 p.Arg306Gln (c.917G>A)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

PLA2G6 p.Arg306Gln

c.917G>A · rs374007706 · VCV1955437

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 57 kb · p 2e-06 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Admixed American · 9/53,216 alleles

Filtering AF 0.00873% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00653%

Overall 0.0023% 36/1,566,844 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0208%	4,802
Admixed Americangrpmax	0.0169%	5,913
African / African-American	0.00811%	12,325
Remaining individualsnot grpmax-eligible	0.00329%	30,411
South Asian	0.00117%	85,272
European (non-Finnish)	0.00104%	96,390

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg306Gln
Coding: c.917G>A
MANE Select: NM_003560
dbSNP: rs374007706
Type: single nucleotide variant
Location: chr22:38132991 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodegeneration with brain iron accumulation 2A

Similar variants

PLA2G6 p.Arg306Trp 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.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-arg306gln (accessed [today's date]).

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