Is PNPLA2 p.Pro484fs (c.1451_1452del) pathogenic?

PNPLA2 p.Pro484fs (c.14511452del) is classified Uncertain significance in PNPLA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). Very rare (popmax 8.73e-05%, nfe); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Pro484fs (c.1451_1452del)?

PNPLA2 p.Pro484fs (c.1451_1452del) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Pro484fs (c.1451_1452del) in the general population?

PNPLA2 p.Pro484fs (c.1451_1452del) is very rare (popmax 8.73e-05%, nfe) (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.Pro484fs

c.1451_1452del · VCV4079755

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.73e-05%, nfe)

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.17	GERP 0.29

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.73e-05% European (non-Finnish) · 1/1,145,750 alleles

Overall 6.52e-05% 1/1,534,034 alleles · very rare exomes 1/1,381,720 · genomes 0/152,314 · joint denominator

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.Pro484fs
Coding: c.1451_1452del
MANE Select: NM_020376
Type: Deletion
Location: chr11:824798 (GRCh38)
Gene constraint: LOEUF 1.221 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.56
Residue 484: 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 p.Pro484Thr Uncertain significance ★ ⚠ same residue
PNPLA2 p.Arg351fs Pathogenic/Likely pathogenic ★★ same condition
PNPLA2 p.Leu264fs Pathogenic/Likely pathogenic ★★ same condition
PNPLA2 p.Phe348fs Pathogenic ★★ same condition
PNPLA2 p.Arg496_Ala501del Uncertain significance ★★ same condition
PNPLA2 p.Asn451fs Uncertain significance ★★ same condition
PNPLA2 p.Lys179del Uncertain significance ★★ same condition
PNPLA2 p.Ala302fs 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/pnpla2-p-pro484fs (accessed [today's date]).

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