Is GBE1 p.Met587Val (c.1759A>G) pathogenic?

GBE1 p.Met587Val (c.1759A>G) is classified Uncertain significance in GBE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-23). AlphaMissense: likely benign (0.1525); Very rare (popmax 0.00346%, sas); Associated with Glycogen storage disease IV, classic hepatic.

What condition is associated with GBE1 p.Met587Val (c.1759A>G)?

GBE1 p.Met587Val (c.1759A>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.Met587Val (c.1759A>G) in the general population?

GBE1 p.Met587Val (c.1759A>G) is very rare (popmax 0.00346%, sas) (gnomAD).

What do computational predictors say about GBE1 p.Met587Val (c.1759A>G)?

AlphaMissense predicts likely benign (score 0.1525) — an in-silico prediction, not a clinical call.

GBE1 p.Met587Val

c.1759A>G · rs572708424 · VCV2154511

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00346%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Glycogen storage disease IV, classic hepatic

Computational evidence

Protein change
AlphaMissense	0.1525	likely benign
REVEL	0.75	pathogenic-leaning
SaProt	LLR -9.70	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 271 kb · p 0.97 · regional, not allelic
Overall
CADD	24.6	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 0.00346% South Asian · 3/86,692 alleles

Filtering AF 0.000919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000455%

Overall 0.000566% 9/1,590,748 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00346%	28,897
European (non-Finnish)	0.000513%	194,975

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.Met587Val
Coding: c.1759A>G
MANE Select: NM_000158
dbSNP: rs572708424
Type: single nucleotide variant
Location: chr3:81536955 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.30 · 3 PDB
Residue 587: 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-met587val (accessed [today's date]).

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