Is PNPLA2 p.Pro486Ser (c.1456C>T) pathogenic?

PNPLA2 p.Pro486Ser (c.1456C>T) is classified Uncertain significance in PNPLA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely benign (0.0682); Very rare (popmax 8.73e-05%, nfe); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Pro486Ser (c.1456C>T)?

PNPLA2 p.Pro486Ser (c.1456C>T) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Pro486Ser (c.1456C>T) in the general population?

PNPLA2 p.Pro486Ser (c.1456C>T) 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.

What do computational predictors say about PNPLA2 p.Pro486Ser (c.1456C>T)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

PNPLA2 p.Pro486Ser

c.1456C>T · rs1554977196 · VCV534195

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.87	GERP -3.2
Regional constraint	o/e 1.10	unconstrained · MANE · 5,140 bp · p 0.0083 · regional, not allelic
Overall
CADD	1.077	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.73e-05% European (non-Finnish) · 1/1,146,064 alleles

Overall 6.52e-05% 1/1,534,538 alleles · very rare exomes 1/1,382,226 · genomes 0/152,312 · 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.Pro486Ser
Coding: c.1456C>T
MANE Select: NM_020376
dbSNP: rs1554977196
Type: single nucleotide variant
Location: chr11:824803 (GRCh38)
Gene constraint: LOEUF 1.221 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.56
Residue 486: 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.Pro486Arg Uncertain significance ★★ ⚠ same residue
PNPLA2 p.Pro486His Uncertain significance ★★ ⚠ same residue
PNPLA2 p.Pro486= Benign/Likely benign ★★ same residue
PNPLA2 p.Pro486_Leu487= Likely benign ★★ 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

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-pro486ser (accessed [today's date]).

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