Is GBE1 p.Val223= (c.669A>G) pathogenic?

GBE1 p.Val223= (c.669A>G) is classified Likely benign in GBE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). Ultra-rare (popmax 0.0125%, amr); Associated with Glycogen storage disease IV, classic hepatic.

What condition is associated with GBE1 p.Val223= (c.669A>G)?

GBE1 p.Val223= (c.669A>G) is associated with Glycogen storage disease IV, classic hepatic, glycogen storage disease due to glycogen branching enzyme deficiency (ClinVar).

How common is GBE1 p.Val223= (c.669A>G) in the general population?

GBE1 p.Val223= (c.669A>G) is ultra-rare (popmax 0.0125%, amr) (gnomAD).

GBE1 p.Val223=

c.669A>G · rs1014444694 · VCV1111188

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, 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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -0.64, phastCons 1
Overall
CADD	7.386	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0125% Admixed American · 7/55,940 alleles

Filtering AF 0.00578% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00413%

Overall 0.000953% 15/1,574,068 alleles · ultra-rare exomes 10/1,421,914 · genomes 5/152,154 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0125%	7,991
African / African-American	0.00137%	72,842
European (non-Finnish)	0.000604%	165,457

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.Val223=
Coding: c.669A>G
MANE Select: NM_000158
dbSNP: rs1014444694
Type: single nucleotide variant
Location: chr3:81648878 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.30 · 3 PDB
Residue 223: an α-helix

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 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
GBE1 c.1803+2T>C 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-val223 (accessed [today's date]).

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