Is GBE1 p.Arg262His (c.785G>A) pathogenic?

GBE1 p.Arg262His (c.785G>A) is classified Conflicting classifications of pathogenicity in GBE1 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2025-09-30). AlphaMissense: ambiguous (0.4596); Ultra-rare (popmax 0.0165%, mid); Associated with adult polyglucosan body disease.

What condition is associated with GBE1 p.Arg262His (c.785G>A)?

GBE1 p.Arg262His (c.785G>A) is associated with adult polyglucosan body disease, glycogen storage disease due to glycogen branching enzyme deficiency (ClinVar).

How common is GBE1 p.Arg262His (c.785G>A) in the general population?

GBE1 p.Arg262His (c.785G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about GBE1 p.Arg262His (c.785G>A)?

AlphaMissense predicts ambiguous (score 0.4596) — an in-silico prediction, not a clinical call.

GBE1 p.Arg262His

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.785G>A · rs369574719 · VCV437422

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

ambiguous

0.4596 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

adult polyglucosan body disease

Computational evidence

Protein change
AlphaMissense	0.4596	ambiguous
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -14.61	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 271 kb · p 0.97 · regional, not allelic
Overall
CADD	32.0	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00318% 51/1,601,384 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
African / African-American	0.0107%	9,326
East Asian	0.00674%	14,847
Remaining individualsnot grpmax-eligible	0.00484%	20,677
European (non-Finnish)	0.00299%	33,478
Admixed American	0.00171%	58,432

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.Arg262His
Coding: c.785G>A
MANE Select: NM_000158
dbSNP: rs369574719
Type: single nucleotide variant
Location: chr3:81642988 (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

adult polyglucosan body disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

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.Arg262Cys 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-arg262his (accessed [today's date]).

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