Is PNPLA2 p.Pro301= (c.903C>T) pathogenic?

PNPLA2 p.Pro301= (c.903C>T) is classified Conflicting classifications of pathogenicity in PNPLA2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-04). Ultra-rare (popmax 0.0363%, nfe); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Pro301= (c.903C>T)?

PNPLA2 p.Pro301= (c.903C>T) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Pro301= (c.903C>T) in the general population?

PNPLA2 p.Pro301= (c.903C>T) is ultra-rare (popmax 0.0363%, 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.Pro301=

c.903C>T · rs141190104 · VCV306302

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, nfe)

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 -9.6	GERP -2.9
Overall
CADD	0.134	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0363% European (non-Finnish) · 425/1,169,302 alleles

Filtering AF 0.0335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0324%

Overall 0.0353% 561/1,590,248 alleles · ultra-rare exomes 486/1,437,988 · genomes 75/152,260 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.196%	509
European (non-Finnish)grpmax	0.0363%	2,751
Remaining individualsnot grpmax-eligible	0.0227%	4,400
African / African-American	0.00402%	24,869
East Asian	0.00229%	43,754
Admixed American	0.00175%	56,998

Finnish 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: PNPLA2
Protein: p.Pro301=
Coding: c.903C>T
MANE Select: NM_020376
dbSNP: rs141190104
Type: single nucleotide variant
Location: chr11:823839 (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.Pro301_Arg303del 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-pro301 (accessed [today's date]).

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