Is PYGL p.Gln577His (c.1731G>C) pathogenic?

PYGL p.Gln577His (c.1731G>C) is classified Uncertain significance in PYGL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.989); Ultra-rare (popmax 0.0164%, mid); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Gln577His (c.1731G>C)?

PYGL p.Gln577His (c.1731G>C) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Gln577His (c.1731G>C) in the general population?

PYGL p.Gln577His (c.1731G>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PYGL p.Gln577His (c.1731G>C)?

AlphaMissense predicts likely pathogenic (score 0.989) — an in-silico prediction, not a clinical call.

PYGL p.Gln577His

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.1731G>C · rs368171220 · VCV1414437

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.989 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease VI

Computational evidence

Protein change
AlphaMissense	0.989	likely pathogenic · top 10% in PYGL
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -11.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP 1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 39 kb · p 0.2 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00279% 45/1,614,078 alleles · ultra-rare exomes 39/1,461,882 · genomes 6/152,196 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.0033%	30,258

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln577His
Coding: c.1731G>C
MANE Select: NM_002863
dbSNP: rs368171220
Type: single nucleotide variant
Location: chr14:50912193 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 577: 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.Gln577Ter Pathogenic/Likely pathogenic ★★ 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-gln577his (accessed [today's date]).

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