Is PYGM p.Lys681fs (c.2040_2041insCC) pathogenic?

PYGM p.Lys681fs (c.20402041insCC) is classified Likely pathogenic in PYGM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). Associated with glycogen storage disease V.

What condition is associated with PYGM p.Lys681fs (c.2040_2041insCC)?

PYGM p.Lys681fs (c.2040_2041insCC) is associated with glycogen storage disease V (ClinVar).

PYGM p.Lys681fs

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

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

c.2040_2041insCC · VCV3600030

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

glycogen storage disease V

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 17 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1

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

Variant & gene context

Gene: PYGM
Protein: p.Lys681fs
Coding: c.2040_2041insCC
MANE Select: NM_005609
Type: Insertion
Location: chr11:64750512 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.41 · 1 PDB
Residue 681: an α-helix; a modified residue (n6-(pyridoxal phosphate)lysine); a UniProt-annotated variant site (in gsd5)

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

Disease context

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

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

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

PYGM p.Lys681Met Uncertain significance ★ ⚠ same residue
PYGM p.Lys681= Likely benign ★ same residue
PYGM c.244-310_244-309insGGGCCTTGGCCTTGCCCTCCTGGGGAGCTCTTGGAGGCGCTTCCACATGTCCTGGCATCCTGCTGGGCTGTGCGG Likely benign ★ same condition
PYGM c.1092+1G>A Likely pathogenic ★★ same condition
PYGM c.1092+1G>C Likely pathogenic ★★ same condition
PYGM c.1239_1239+1delinsAT Pathogenic ★★ same condition
PYGM c.1239+1G>A Pathogenic/Likely pathogenic ★★ same condition
PYGM c.1240-2A>G 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/pygm-p-lys681fs (accessed [today's date]).

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