Is GBE1 p.Arg262Cys (c.784C>T) pathogenic?

GBE1 p.Arg262Cys (c.784C>T) is classified Conflicting classifications of pathogenicity in GBE1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-02). AlphaMissense: likely pathogenic (0.5983); Very rare (popmax 0.00291%, nfe); Associated with glycogen storage disease due to glycogen branching enzyme deficiency.

What condition is associated with GBE1 p.Arg262Cys (c.784C>T)?

GBE1 p.Arg262Cys (c.784C>T) is associated with glycogen storage disease due to glycogen branching enzyme deficiency, adult polyglucosan body disease, glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form (ClinVar).

How common is GBE1 p.Arg262Cys (c.784C>T) in the general population?

GBE1 p.Arg262Cys (c.784C>T) is very rare (popmax 0.00291%, nfe) (gnomAD).

What do computational predictors say about GBE1 p.Arg262Cys (c.784C>T)?

AlphaMissense predicts likely pathogenic (score 0.5983) — an in-silico prediction, not a clinical call.

GBE1 p.Arg262Cys

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.784C>T · rs137852893 · VCV2791

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.5983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00291%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease due to glycogen branching enzyme deficiency

Computational evidence

Protein change
AlphaMissense	0.5983	likely pathogenic
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -15.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.96 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 271 kb · p 0.97 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00291% European (non-Finnish) · 34/1,169,752 alleles

Filtering AF 0.00209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.00213% 34/1,598,882 alleles · very rare exomes 34/1,446,824 · genomes 0/152,058 · 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.Arg262Cys
Coding: c.784C>T
MANE Select: NM_000158
dbSNP: rs137852893
Type: single nucleotide variant
Location: chr3:81642989 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.30 · 3 PDB
Residue 262: an α-helix

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: adult polyglucosan body disease 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.Arg262His Conflicting classifications of pathogenicity ★ ⚠ 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-arg262cys (accessed [today's date]).

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