Is PNPLA2 p.Ser288Trp (c.863C>G) pathogenic?

PNPLA2 p.Ser288Trp (c.863C>G) is classified Benign/Likely benign in PNPLA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0894); Low-frequency (popmax 1.01%, eas); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Ser288Trp (c.863C>G)?

PNPLA2 p.Ser288Trp (c.863C>G) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Ser288Trp (c.863C>G) in the general population?

PNPLA2 p.Ser288Trp (c.863C>G) is low-frequency (popmax 1.01%, eas) (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.Ser288Trp (c.863C>G)?

AlphaMissense predicts likely benign (score 0.0894) — an in-silico prediction, not a clinical call.

PNPLA2 p.Ser288Trp

c.863C>G · rs200088893 · VCV465800

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0894 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
AlphaMissense	0.0894	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -8.28	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 -1.7	GERP -2.9
Regional constraint	o/e 1.10	unconstrained · MANE · 5,140 bp · p 0.0083 · regional, not allelic
Overall
CADD	5.738	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.01% East Asian · 449/44,542 alleles

Filtering AF 0.931% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.901%

Overall 0.0309% 496/1,605,188 alleles · low-frequency exomes 422/1,453,114 · genomes 74/152,074 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.01%	99
Remaining individualsnot grpmax-eligible	0.0435%	2,301
South Asian	0.0178%	5,626
Middle Eastern	0.0165%	6,050
African / African-American	0.00267%	37,438
Admixed American	0.00169%	59,178

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.Ser288Trp
Coding: c.863C>G
MANE Select: NM_020376
dbSNP: rs200088893
Type: single nucleotide variant
Location: chr11:823799 (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 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-ser288trp (accessed [today's date]).

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