Is PNPLA2 p.Ser199= (c.597C>T) pathogenic?

PNPLA2 p.Ser199= (c.597C>T) is classified Conflicting classifications of pathogenicity in PNPLA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.0383%, amr); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Ser199= (c.597C>T)?

PNPLA2 p.Ser199= (c.597C>T) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Ser199= (c.597C>T) in the general population?

PNPLA2 p.Ser199= (c.597C>T) is ultra-rare (popmax 0.0383%, amr) (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.Ser199=

c.597C>T · rs552415591 · VCV772343

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.7	GERP -4.7
Overall
CADD	7.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0383% Admixed American · 23/60,026 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.0018% 29/1,614,034 alleles · ultra-rare exomes 11/1,461,682 · genomes 18/152,352 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,610
Remaining individualsnot grpmax-eligible	0.0096%	10,417

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.Ser199=
Coding: c.597C>T
MANE Select: NM_020376
dbSNP: rs552415591
Type: single nucleotide variant
Location: chr11:822507 (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-ser199 (accessed [today's date]).

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