Is PNPLA2 p.Pro464= (c.1392C>T) pathogenic?

PNPLA2 p.Pro464= (c.1392C>T) is classified Likely benign in PNPLA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-04). Ultra-rare (popmax 0.0167%, mid); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Pro464= (c.1392C>T)?

PNPLA2 p.Pro464= (c.1392C>T) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Pro464= (c.1392C>T) in the general population?

PNPLA2 p.Pro464= (c.1392C>T) is ultra-rare (popmax 0.0167%, mid) (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.Pro464=

c.1392C>T · rs779795122 · VCV798576

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

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 0.59	GERP -3.2, phastCons 0.043
Overall
CADD	0.259	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/6,006 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00117%

Overall 0.00184% 29/1,577,192 alleles · ultra-rare exomes 26/1,425,016 · genomes 3/152,176 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,006
Finnishnot grpmax-eligible	0.00423%	23,636
European (non-Finnish)	0.00205%	48,724
Remaining individualsnot grpmax-eligible	0.00163%	61,380
African / African-American	0.00135%	74,294

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.Pro464=
Coding: c.1392C>T
MANE Select: NM_020376
dbSNP: rs779795122
Type: single nucleotide variant
Location: chr11:824739 (GRCh38)
Gene constraint: LOEUF 1.221 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.56
Residue 464: 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-pro464 (accessed [today's date]).

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