Is GBE1 p.Ile334Val (c.1000A>G) pathogenic?

GBE1 p.Ile334Val (c.1000A>G) is classified Benign in GBE1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0514); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with adult polyglucosan body disease.

What condition is associated with GBE1 p.Ile334Val (c.1000A>G)?

GBE1 p.Ile334Val (c.1000A>G) is associated with adult polyglucosan body disease, glycogen storage disease due to glycogen branching enzyme deficiency (ClinVar).

What do computational predictors say about GBE1 p.Ile334Val (c.1000A>G)?

AlphaMissense predicts likely benign (score 0.0514) — an in-silico prediction, not a clinical call.

GBE1 p.Ile334Val

Q: How common is GBE1 p.Ile334Val (c.1000A>G) in the general population?

GBE1 p.Ile334Val (c.1000A>G) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1000A>G · rs2172397 · VCV1168034

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0514 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adult polyglucosan body disease

Computational evidence

Protein change
AlphaMissense	0.0514	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -1.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 271 kb · p 0.97 · regional, not allelic
Overall
CADD	16.56	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 100% East Asian · 42,540/42,546 alleles

Filtering AF 99.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.9%

Overall 97.2% 1,463,903/1,505,534 alleles · common exomes 1,314,913/1,353,300 · genomes 148,990/152,234 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
African / African-American	99.6%	1
Amishnot grpmax-eligible	99.6%	1
Admixed American	98.9%	1
Ashkenazi Jewishnot grpmax-eligible	98.5%	1
Remaining individualsnot grpmax-eligible	97.4%	1
European (non-Finnish)	97%	1
South Asian	96.4%	1
Middle Eastern	96.2%	1
Finnishnot grpmax-eligible	95.8%	1

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.Ile334Val
Coding: c.1000A>G
MANE Select: NM_000158
dbSNP: rs2172397
Type: single nucleotide variant
Location: chr3:81594016 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.30 · 3 PDB
Residue 334: a UniProt-annotated variant site (in); an α-helix; a binding site

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.Ile334fs Likely pathogenic ★ same residue
GBE1 p.Ile334= Benign ★ 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

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-ile334val (accessed [today's date]).

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