Is PNPLA2 p.Ala482= (c.1446C>G) pathogenic?

PNPLA2 p.Ala482= (c.1446C>G) is classified Conflicting classifications of pathogenicity in PNPLA2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-27). Very rare (popmax 0.00549%, afr); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Ala482= (c.1446C>G)?

PNPLA2 p.Ala482= (c.1446C>G) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Ala482= (c.1446C>G) in the general population?

PNPLA2 p.Ala482= (c.1446C>G) is very rare (popmax 0.00549%, afr) (gnomAD).

How is Neutral lipid storage disease with myopathy inherited?

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

PNPLA2 p.Ala482=

c.1446C>G · rs768610141 · VCV1140012

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00549%, afr)

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -0.98
Overall
CADD	2.728	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% African / African-American · 4/72,840 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.000587% 9/1,532,612 alleles · very rare exomes 5/1,380,438 · genomes 4/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00549%	18,210
Admixed American	0.00397%	25,208
South Asian	0.00119%	83,956
European (non-Finnish)	0.000175%	572,541

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.Ala482=
Coding: c.1446C>G
MANE Select: NM_020376
dbSNP: rs768610141
Type: single nucleotide variant
Location: chr11:824793 (GRCh38)
Gene constraint: LOEUF 1.221 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.56
Residue 482: the 'disordered' region

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 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
PNPLA2 c.*383C>T Uncertain significance ★★ same condition
PNPLA2 p.Ala263Ser Uncertain significance ★★ ⚠ same condition
PNPLA2 p.Ala263Thr 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-ala482 (accessed [today's date]).

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