Is PYGL p.Lys640= (c.1920G>A) pathogenic?

PYGL p.Lys640= (c.1920G>A) is classified Conflicting classifications of pathogenicity in PYGL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-20). Ultra-rare (popmax 0.0683%, nfe); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Lys640= (c.1920G>A)?

PYGL p.Lys640= (c.1920G>A) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Lys640= (c.1920G>A) in the general population?

PYGL p.Lys640= (c.1920G>A) is ultra-rare (popmax 0.0683%, nfe) (gnomAD).

PYGL p.Lys640=

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.1920G>A · rs140296036 · VCV313321

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0683%, nfe)

Conditions

glycogen storage disease VI

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.063, phastCons 1
Overall
CADD	9.007	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0683% European (non-Finnish) · 806/1,180,014 alleles

Filtering AF 0.0644% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0628%

Overall 0.0525% 847/1,614,174 alleles · ultra-rare exomes 782/1,461,868 · genomes 65/152,306 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0683%	1,464
Remaining individualsnot grpmax-eligible	0.04%	2,500
Middle Eastern	0.0165%	6,062
Admixed American	0.0117%	8,576
African / African-American	0.008%	12,506
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Finnishnot grpmax-eligible	0.00156%	64,034

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.Lys640=
Coding: c.1920G>A
MANE Select: NM_002863
dbSNP: rs140296036
Type: single nucleotide variant
Location: chr14:50911779 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 640: 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-lys640 (accessed [today's date]).

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