Is GBE1 p.Pro93Leu (c.278C>T) pathogenic?

GBE1 p.Pro93Leu (c.278C>T) is classified Uncertain significance in GBE1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-04-30). AlphaMissense: ambiguous (0.5047); Rare (popmax 0.315%, mid); Associated with Glycogen storage disease IV, classic hepatic.

What condition is associated with GBE1 p.Pro93Leu (c.278C>T)?

GBE1 p.Pro93Leu (c.278C>T) is associated with Glycogen storage disease IV, classic hepatic, glycogen storage disease due to glycogen branching enzyme deficiency (ClinVar).

How common is GBE1 p.Pro93Leu (c.278C>T) in the general population?

GBE1 p.Pro93Leu (c.278C>T) is rare (popmax 0.315%, mid) (gnomAD).

What do computational predictors say about GBE1 p.Pro93Leu (c.278C>T)?

AlphaMissense predicts ambiguous (score 0.5047) — an in-silico prediction, not a clinical call.

GBE1 p.Pro93Leu

c.278C>T · rs200746350 · VCV1308328

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.5047 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.315%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Glycogen storage disease IV, classic hepatic

Computational evidence

Protein change
AlphaMissense	0.5047	ambiguous
REVEL	0.676	pathogenic-leaning
SaProt	LLR -14.88	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 271 kb · p 0.97 · regional, not allelic
Overall
CADD	33.0	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 0.315% Middle Eastern · 19/6,030 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.172%

Overall 0.0204% 326/1,598,090 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.315%	317
Ashkenazi Jewishnot grpmax-eligible	0.0478%	2,091
Remaining individualsnot grpmax-eligible	0.0436%	2,294
European (non-Finnish)	0.0202%	4,949
African / African-American	0.0134%	7,441
Finnishnot grpmax-eligible	0.00944%	10,598
South Asian	0.00803%	12,453
Admixed American	0.00694%	14,403
East Asian	0.00453%	22,089

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.Pro93Leu
Coding: c.278C>T
MANE Select: NM_000158
dbSNP: rs200746350
Type: single nucleotide variant
Location: chr3:81705479 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.30 · 3 PDB
Residue 93: a binding site

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.Pro93= Likely 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
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-pro93leu (accessed [today's date]).

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