Is PNPLA2 p.Pro291= (c.873C>G) pathogenic?

PNPLA2 p.Pro291= (c.873C>G) is classified Benign/Likely benign in PNPLA2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 42.1%, sas) — too common for a highly-penetrant pathogenic allele; Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Pro291= (c.873C>G)?

PNPLA2 p.Pro291= (c.873C>G) is associated with neutral lipid storage myopathy (ClinVar).

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.Pro291=

Q: How common is PNPLA2 p.Pro291= (c.873C>G) in the general population?

PNPLA2 p.Pro291= (c.873C>G) is common (popmax 42.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.873C>G · rs1135628 · VCV261248

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 42.1%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11	GERP -2.9
Overall
CADD	0.079	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 42.1% South Asian · 37,742/89,614 alleles

Filtering AF 41.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 41.6%

Overall 24.7% 395,999/1,601,182 alleles · common exomes 363,517/1,449,164 · genomes 32,482/152,018 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	42.1%	2
Ashkenazi Jewishnot grpmax-eligible	39.1%	3
Middle Eastern	37.5%	3
East Asian	37%	3
Remaining individualsnot grpmax-eligible	26.8%	4
Finnishnot grpmax-eligible	24.8%	4
European (non-Finnish)	23.6%	4
Amishnot grpmax-eligible	21.4%	5
Admixed American	19.8%	5
African / African-American	9.57%	10

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.Pro291=
Coding: c.873C>G
MANE Select: NM_020376
dbSNP: rs1135628
Type: single nucleotide variant
Location: chr11:823809 (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.Pro291Ser Uncertain significance ★★ ⚠ 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
PNPLA2 c.*383C>T Uncertain significance ★★ same condition
PNPLA2 p.Ala263Ser 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-pro291 (accessed [today's date]).

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