Is PNPLA2 p.Pro409Gln (c.1226C>A) pathogenic?

PNPLA2 p.Pro409Gln (c.1226C>A) is classified Uncertain significance in PNPLA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely benign (0.1332); Rare (popmax 0.127%, sas); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Pro409Gln (c.1226C>A)?

PNPLA2 p.Pro409Gln (c.1226C>A) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Pro409Gln (c.1226C>A) in the general population?

PNPLA2 p.Pro409Gln (c.1226C>A) is rare (popmax 0.127%, sas) (gnomAD).

How is Neutral lipid storage disease with myopathy inherited?

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

What do computational predictors say about PNPLA2 p.Pro409Gln (c.1226C>A)?

AlphaMissense predicts likely benign (score 0.1332) — an in-silico prediction, not a clinical call.

PNPLA2 p.Pro409Gln

c.1226C>A · rs549863849 · VCV2082748

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1332 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.127%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
AlphaMissense	0.1332	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.95	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 3.1	GERP 0.43, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 5,140 bp · p 0.0083 · regional, not allelic
Overall
CADD	19.6	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 0.127% South Asian · 111/87,300 alleles

Filtering AF 0.108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.008% 126/1,575,060 alleles · rare exomes 117/1,422,820 · genomes 9/152,240 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.127%	786
Remaining individualsnot grpmax-eligible	0.00327%	30,568
African / African-American	0.00134%	74,500
European (non-Finnish)	0.00103%	97,104

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: PNPLA2
Protein: p.Pro409Gln
Coding: c.1226C>A
MANE Select: NM_020376
dbSNP: rs549863849
Type: single nucleotide variant
Location: chr11:824573 (GRCh38)
Gene constraint: LOEUF 1.221 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.56

Full PNPLA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neutral lipid storage myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Neutral lipid storage disease with myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

PNPLA2 p.Pro409Arg Uncertain significance ★★ ⚠ same residue
PNPLA2 p.Pro409Leu Uncertain significance ★ ⚠ same residue
PNPLA2 p.Pro409= Likely benign ★ same residue
PNPLA2 c.187+1G>C Pathogenic/Likely pathogenic ★★ same condition
PNPLA2 c.757+1G>T Pathogenic ★★ same condition
PNPLA2 p.Arg221Pro Pathogenic ★★ same condition
PNPLA2 p.Pro195Leu Pathogenic ★★ same condition
PNPLA2 c.1175+3G>A Uncertain significance ★★ 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/pnpla2-p-pro409gln (accessed [today's date]).

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