Is PYGL p.Ser15fs (c.25_44dup) pathogenic?

PYGL p.Ser15fs (c.2544dup) is classified Pathogenic in PYGL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-08). Very rare (popmax 0.00133%, afr); Associated with glycogen storage disease VI.

What condition is associated with PYGL p.Ser15fs (c.25_44dup)?

PYGL p.Ser15fs (c.25_44dup) is associated with glycogen storage disease VI (ClinVar).

How common is PYGL p.Ser15fs (c.25_44dup) in the general population?

PYGL p.Ser15fs (c.25_44dup) is very rare (popmax 0.00133%, afr) (gnomAD).

PYGL p.Ser15fs

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.25_44dup · rs786204785 · VCV189242

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

glycogen storage disease VI

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 0.84, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,932 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,500 alleles · very rare exomes 4/1,461,262 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,932
European (non-Finnish)	0.000339%	294,958

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.Ser15fs
Coding: c.25_44dup
MANE Select: NM_002863
dbSNP: rs786204785
Type: Duplication
Location: chr14:50944359 (GRCh38)
Gene constraint: LOEUF 1.048 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 19 PDB
Residue 15: a β-strand; a modified residue (phosphoserine; by phk; in form phosphorylase a)

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.Leu305fs Pathogenic ★★ same condition
PYGL p.Arg12fs Pathogenic ★ same condition
PYGL p.Asn408fs Likely pathogenic ★ same condition
PYGL p.Leu137fs Likely pathogenic ★ same condition
PYGL p.Ser639fs Likely pathogenic ★ same condition
PYGL p.Ser752fs Likely pathogenic ★ same condition
PYGL c.1404-1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGL c.1620+1G>A 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-ser15fs (accessed [today's date]).

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