Is GBE1 p.Arg468Ser (c.1402C>A) pathogenic?

GBE1 p.Arg468Ser (c.1402C>A) is classified Uncertain significance in GBE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-22). AlphaMissense: likely pathogenic (0.9902); Very rare (popmax 0.0017%, amr); Associated with Glycogen storage disease IV, classic hepatic.

What condition is associated with GBE1 p.Arg468Ser (c.1402C>A)?

GBE1 p.Arg468Ser (c.1402C>A) is associated with Glycogen storage disease IV, classic hepatic, glycogen storage disease due to glycogen branching enzyme deficiency (ClinVar).

How common is GBE1 p.Arg468Ser (c.1402C>A) in the general population?

GBE1 p.Arg468Ser (c.1402C>A) is very rare (popmax 0.0017%, amr) (gnomAD).

What do computational predictors say about GBE1 p.Arg468Ser (c.1402C>A)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

GBE1 p.Arg468Ser

c.1402C>A · rs776526697 · VCV967587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Glycogen storage disease IV, classic hepatic

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic · top 2% in GBE1
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -10.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 271 kb · p 0.97 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% Admixed American · 1/58,702 alleles

Overall 6.23e-05% 1/1,605,880 alleles · very rare exomes 1/1,454,160 · genomes 0/151,720 · 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.Arg468Ser
Coding: c.1402C>A
MANE Select: NM_000158
dbSNP: rs776526697
Type: single nucleotide variant
Location: chr3:81581209 (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.Arg468His Uncertain significance ★ ⚠ same residue
GBE1 p.Arg468Gly Uncertain significance ⚠ same residue
GBE1 p.Arg468fs Pathogenic ★★ same residue
GBE1 p.Arg468Cys 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

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-arg468ser (accessed [today's date]).

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