Is PYGM p.Pro489Arg (c.1466C>G) pathogenic?

PYGM p.Pro489Arg (c.1466C>G) is classified Pathogenic/Likely pathogenic in PYGM (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.9632); Very rare (popmax 0.00949%, nfe); Associated with glycogen storage disease V.

What condition is associated with PYGM p.Pro489Arg (c.1466C>G)?

PYGM p.Pro489Arg (c.1466C>G) is associated with glycogen storage disease V (ClinVar).

How common is PYGM p.Pro489Arg (c.1466C>G) in the general population?

PYGM p.Pro489Arg (c.1466C>G) is very rare (popmax 0.00949%, nfe) (gnomAD).

What do computational predictors say about PYGM p.Pro489Arg (c.1466C>G)?

AlphaMissense predicts likely pathogenic (score 0.9632) — an in-silico prediction, not a clinical call.

PYGM p.Pro489Arg

Q: How is Glycogen storage disease due to muscle glycogen phosphorylase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1466C>G · rs398124209 · VCV95291

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9632 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00949%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease V

Computational evidence

Protein change
AlphaMissense	0.9632	likely pathogenic ✓ concordant with ClinVar
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -17.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.00017 · regional, not allelic
Overall
CADD	29.6	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 0.00949% European (non-Finnish) · 112/1,179,992 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.0075% 121/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00949%	10,536
African / African-American	0.00667%	14,987
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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: PYGM
Protein: p.Pro489Arg
Coding: c.1466C>G
MANE Select: NM_005609
dbSNP: rs398124209
Type: single nucleotide variant
Location: chr11:64753125 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.41 · 1 PDB
Residue 489: a UniProt-annotated variant site (in gsd5)

Full PYGM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease V — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to muscle glycogen phosphorylase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

PYGM p.Pro489Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PYGM c.1092+1G>A Likely pathogenic ★★ same condition
PYGM c.1092+1G>C Likely pathogenic ★★ same condition
PYGM c.1239+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1240-2A>G Likely pathogenic ★★ same condition
PYGM c.1403+1G>A Pathogenic ★★ same condition
PYGM c.1768+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1768+2T>G Pathogenic/Likely 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/pygm-p-pro489arg (accessed [today's date]).

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