Is PNPLA2 p.Pro477Arg (c.1430C>G) pathogenic?

PNPLA2 p.Pro477Arg (c.1430C>G) is classified Benign/Likely benign in PNPLA2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0692); Low-frequency (popmax 3.21%, afr); Associated with neutral lipid storage myopathy.

What condition is associated with PNPLA2 p.Pro477Arg (c.1430C>G)?

PNPLA2 p.Pro477Arg (c.1430C>G) is associated with neutral lipid storage myopathy (ClinVar).

How common is PNPLA2 p.Pro477Arg (c.1430C>G) in the general population?

PNPLA2 p.Pro477Arg (c.1430C>G) is low-frequency (popmax 3.21%, afr) (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.Pro477Arg (c.1430C>G)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

PNPLA2 p.Pro477Arg

c.1430C>G · rs142588621 · VCV261234

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.21%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neutral lipid storage myopathy

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -7.60	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 0.33	GERP -0.32
Regional constraint	o/e 1.10	unconstrained · MANE · 5,140 bp · p 0.0083 · regional, not allelic
Overall
CADD	14.1	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 3.21% African / African-American · 2,357/73,376 alleles

Filtering AF 3.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.06%

Overall 0.189% 2,915/1,542,572 alleles · low-frequency exomes 1,512/1,390,292 · genomes 1,403/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.21%	31
Admixed American	0.291%	343
Remaining individualsnot grpmax-eligible	0.262%	381
Middle Eastern	0.167%	599
European (non-Finnish)	0.0201%	4,981
South Asian	0.00943%	10,606

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.Pro477Arg
Coding: c.1430C>G
MANE Select: NM_020376
dbSNP: rs142588621
Type: single nucleotide variant
Location: chr11:824777 (GRCh38)
Gene constraint: LOEUF 1.221 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.56
Residue 477: 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.Pro477Ala Uncertain significance ★ ⚠ same residue
PNPLA2 p.Pro477Leu Conflicting classifications of pathogenicity ★ ⚠ 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
PNPLA2 c.1175+3G>A Uncertain significance ★★ same condition
PNPLA2 c.*383C>T 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-pro477arg (accessed [today's date]).

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