Is GBE1 p.Trp548Ter (c.1643G>A) pathogenic?

GBE1 p.Trp548Ter (c.1643G>A) is classified Pathogenic in GBE1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-16). Very rare (popmax 0.00259%, sas); Associated with glycogen storage disease due to glycogen branching enzyme deficiency.

What condition is associated with GBE1 p.Trp548Ter (c.1643G>A)?

GBE1 p.Trp548Ter (c.1643G>A) is associated with glycogen storage disease due to glycogen branching enzyme deficiency, glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form (ClinVar).

How common is GBE1 p.Trp548Ter (c.1643G>A) in the general population?

GBE1 p.Trp548Ter (c.1643G>A) is very rare (popmax 0.00259%, sas) (gnomAD).

GBE1 p.Trp548Ter

Q: How is Glycogen storage disease due to glycogen branching enzyme deficiency inherited?

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

c.1643G>A · rs137852894 · VCV2793

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00259%, sas)

Conditions

glycogen storage disease due to glycogen branching enzyme deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 16
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Overall
CADD	42.0	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 0.00259% South Asian · 2/77,176 alleles

Filtering AF 0.00043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000161%

Overall 0.000129% 2/1,545,246 alleles · very rare exomes 2/1,393,100 · genomes 0/152,146 · joint denominator

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.Trp548Ter
Coding: c.1643G>A
MANE Select: NM_000158
dbSNP: rs137852894
Type: single nucleotide variant
Location: chr3:81537071 (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 due to glycogen branching enzyme deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form

For Glycogen storage disease due to glycogen branching enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

GBE1 p.Trp548Cys Uncertain significance ★★ ⚠ same residue
GBE1 c.1109-1G>T Likely pathogenic ★★ same condition
GBE1 c.1236+1G>A Likely pathogenic ★★ same condition
GBE1 c.1336-1G>A Pathogenic/Likely pathogenic ★★ same condition
GBE1 c.143+1G>A Pathogenic ★★ same condition
GBE1 c.143+2T>C Pathogenic/Likely pathogenic ★★ same condition
GBE1 c.144-1G>C Pathogenic/Likely pathogenic ★★ same condition
GBE1 c.1618+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/gbe1-p-trp548ter (accessed [today's date]).

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