Is PYGL p.Arg533Gln (c.1598G>A) pathogenic?

PYGL p.Arg533Gln (c.1598G>A) is classified Uncertain significance in PYGL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-04). AlphaMissense: likely benign (0.0907); Ultra-rare (popmax 0.0834%, sas); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Arg533Gln (c.1598G>A)?

PYGL p.Arg533Gln (c.1598G>A) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Arg533Gln (c.1598G>A) in the general population?

PYGL p.Arg533Gln (c.1598G>A) is ultra-rare (popmax 0.0834%, sas) (gnomAD).

What do computational predictors say about PYGL p.Arg533Gln (c.1598G>A)?

AlphaMissense predicts likely benign (score 0.0907) — an in-silico prediction, not a clinical call.

PYGL p.Arg533Gln

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

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

c.1598G>A · rs778002035 · VCV1510583

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0834%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.0907	likely benign
REVEL	0.483	indeterminate
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	24.4	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 0.0834% South Asian · 76/91,086 alleles

Filtering AF 0.0683% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0628%

Overall 0.00582% 94/1,613,808 alleles · ultra-rare exomes 87/1,461,606 · genomes 7/152,202 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0834%	1,199
Middle Eastern	0.0329%	3,038
African / African-American	0.00667%	14,985
East Asian	0.00446%	22,444
Admixed American	0.00167%	60,002
European (non-Finnish)	0.000678%	147,480

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: PYGL
Protein: p.Arg533Gln
Coding: c.1598G>A
MANE Select: NM_002863
dbSNP: rs778002035
Type: single nucleotide variant
Location: chr14:50913051 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 533: an α-helix

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

Disease context

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

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

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PYGL p.Arg533Trp Uncertain significance ★ ⚠ same residue
PYGL c.1404-1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGL c.1620+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGL c.1620+1G>C Pathogenic ★★ same condition
PYGL c.1768+1G>A Pathogenic ★★ same condition
PYGL c.772+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGL p.Arg576Ter Pathogenic ★★ same condition
PYGL p.Arg94Ter 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/pygl-p-arg533gln (accessed [today's date]).

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