Is PYGL p.His583Arg (c.1748A>G) pathogenic?

PYGL p.His583Arg (c.1748A>G) is classified Uncertain significance in PYGL (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-10). AlphaMissense: ambiguous (0.5104); Very rare (popmax 0.00534%, afr); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.His583Arg (c.1748A>G)?

PYGL p.His583Arg (c.1748A>G) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.His583Arg (c.1748A>G) in the general population?

PYGL p.His583Arg (c.1748A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about PYGL p.His583Arg (c.1748A>G)?

AlphaMissense predicts ambiguous (score 0.5104) — an in-silico prediction, not a clinical call.

PYGL p.His583Arg

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.1748A>G · rs375136222 · VCV1040590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.5104	ambiguous
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -14.11	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	24.2	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 0.00534% African / African-American · 4/74,934 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00112% 18/1,614,110 alleles · very rare exomes 16/1,461,894 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,734
East Asian	0.00445%	22,447
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.000847%	118,005

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.His583Arg
Coding: c.1748A>G
MANE Select: NM_002863
dbSNP: rs375136222
Type: single nucleotide variant
Location: chr14:50912176 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 583: 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 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
PYGL p.Gln577Ter 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/pygl-p-his583arg (accessed [today's date]).

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