Is PNPLA2 p.Phe12= (c.36C>T) pathogenic?

PNPLA2 p.Phe12= (c.36C>T) is classified Conflicting classifications of pathogenicity in PNPLA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-12). Very rare (popmax 0.00372%, nfe); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Phe12= (c.36C>T)?

PNPLA2 p.Phe12= (c.36C>T) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Phe12= (c.36C>T) in the general population?

PNPLA2 p.Phe12= (c.36C>T) is very rare (popmax 0.00372%, 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.Phe12=

c.36C>T · rs750233571 · VCV881329

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00372%, 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 4.4	GERP 0.9, phastCons 1
Overall
CADD	15.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00372% European (non-Finnish) · 42/1,129,718 alleles

Filtering AF 0.00278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00247%

Overall 0.00285% 43/1,509,906 alleles · very rare exomes 39/1,357,852 · genomes 4/152,054 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00372%	26,898
African / African-American	0.00145%	69,002

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.Phe12=
Coding: c.36C>T
MANE Select: NM_020376
dbSNP: rs750233571
Type: single nucleotide variant
Location: chr11:819754 (GRCh38)
Gene constraint: LOEUF 1.221 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.56
Residue 12: the pnpla domain

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-phe12 (accessed [today's date]).

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