Is PNPLA2 p.Pro258Ser (c.772C>T) pathogenic?

PNPLA2 p.Pro258Ser (c.772C>T) is classified Uncertain significance in PNPLA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely benign (0.1512); Very rare (popmax 0.0017%, nfe); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Pro258Ser (c.772C>T)?

PNPLA2 p.Pro258Ser (c.772C>T) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Pro258Ser (c.772C>T) in the general population?

PNPLA2 p.Pro258Ser (c.772C>T) is very rare (popmax 0.0017%, 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.Pro258Ser (c.772C>T)?

AlphaMissense predicts likely benign (score 0.1512) — an in-silico prediction, not a clinical call.

PNPLA2 p.Pro258Ser

c.772C>T · rs1246963580 · VCV949625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
AlphaMissense	0.1512	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -5.94	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 3.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 5,140 bp · p 0.0083 · regional, not allelic
Overall
CADD	18.17	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 0.0017% European (non-Finnish) · 20/1,177,830 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000901%

Overall 0.00137% 22/1,607,882 alleles · very rare exomes 17/1,455,748 · genomes 5/152,134 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0017%	58,891
Remaining individualsnot grpmax-eligible	0.00161%	62,174
African / African-American	0.00134%	74,824

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.Pro258Ser
Coding: c.772C>T
MANE Select: NM_020376
dbSNP: rs1246963580
Type: single nucleotide variant
Location: chr11:823708 (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-pro258ser (accessed [today's date]).

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