Is GBE1 p.Ser559fs (c.1675_1676dup) pathogenic?

GBE1 p.Ser559fs (c.16751676dup) is classified Pathogenic/Likely pathogenic in GBE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-20). Very rare (popmax 0.00184%, amr); Associated with Glycogen storage disease IV, classic hepatic.

What condition is associated with GBE1 p.Ser559fs (c.1675_1676dup)?

GBE1 p.Ser559fs (c.1675_1676dup) is associated with Glycogen storage disease IV, classic hepatic, glycogen storage disease due to glycogen branching enzyme deficiency (ClinVar).

How common is GBE1 p.Ser559fs (c.1675_1676dup) in the general population?

GBE1 p.Ser559fs (c.1675_1676dup) is very rare (popmax 0.00184%, amr) (gnomAD).

GBE1 p.Ser559fs

c.1675_1676dup · rs1412857849 · VCV1069462

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00184%, amr)

Conditions

Glycogen storage disease IV, classic hepatic

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 13 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.6	GERP -4.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00184% Admixed American · 1/54,286 alleles

Overall 0.000127% 2/1,578,894 alleles · very rare exomes 2/1,426,850 · genomes 0/152,044 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00184%	54,286
European (non-Finnish)	8.58e-05%	1,165,511

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: GBE1
Protein: p.Ser559fs
Coding: c.1675_1676dup
MANE Select: NM_000158
dbSNP: rs1412857849
Type: Microsatellite
Location: chr3:81537037 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.30 · 3 PDB

Full GBE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Glycogen storage disease IV, classic hepatic — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease due to glycogen branching enzyme deficiency

Similar variants

GBE1 p.Ser559Ile Uncertain significance ★ ⚠ same residue
GBE1 p.Ser559= Likely benign ★ same residue
GBE1 p.Ser559Arg Uncertain significance ⚠ same residue
GBE1 c.314-13_314-11del Likely benign ★★ same condition
GBE1 p.Val288fs Likely pathogenic ★ same condition
GBE1 p.Leu622del Uncertain significance ★ same condition
GBE1 c.555+11_555+13del Likely benign ★ same condition
GBE1 c.691+15_691+16del Likely benign ★ 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/gbe1-p-ser559fs (accessed [today's date]).

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