glycogen storage disease Ib

Summary

glycogen storage disease Ib (MONDO:0009288) is a disease caused by SLC37A4 (GenCC Definitive), with 3 cohort genes and 6 clinical trials. Top therapeutic interventions include empagliflozin, lactic acid, and d-lactic acid.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SLC37A4 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,027
• Phenotypes (HPO): 61
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		150	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	4.1	Israel	Validated
Prevalence at birth	1-9 / 100 000	8	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

61 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001538	Protuberant abdomen	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0002149	Hyperuricemia	Very frequent (80-99%)
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0003077	Hyperlipidemia	Very frequent (80-99%)
HP:0003124	Hypercholesterolemia	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0006568	Increased hepatic glycogen content	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000105	Enlarged kidney	Frequent (30-79%)
HP:0000147	Polycystic ovaries	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000311	Round face	Frequent (30-79%)
HP:0000858	Irregular menstruation	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001397	Hepatic steatosis	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001733	Pancreatitis	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0010974	Abnormal myeloid leukocyte morphology	Frequent (30-79%)
HP:0100279	Ulcerative colitis	Frequent (30-79%)
HP:0100512	Low levels of vitamin D	Frequent (30-79%)
HP:0100646	Thyroiditis	Frequent (30-79%)
HP:0410252	Chronic neutropenia	Frequent (30-79%)
HP:0000093	Proteinuria	Occasional (5-29%)
HP:0000121	Nephrocalcinosis	Occasional (5-29%)
HP:0000132	Menorrhagia	Occasional (5-29%)
HP:0000155	Oral ulcer	Occasional (5-29%)
HP:0000230	Gingivitis	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0000670	Carious teeth	Occasional (5-29%)
HP:0000696	Delayed eruption of permanent teeth	Occasional (5-29%)
HP:0000704	Periodontitis	Occasional (5-29%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0001114	Xanthelasma	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002037	Inflammation of the large intestine	Occasional (5-29%)
HP:0002173	Hypoglycemic seizures	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease Ib
Mondo ID	MONDO:0009288
MeSH	C562594
OMIM	232220, 232240
Orphanet	79259
DOID	DOID:0081330, DOID:0081331
NCIT	C122661
SNOMED CT	237965005, 30102006
UMLS	C0268146
MedGen	78644
GARD	0002515
Is cancer (heuristic)	no

Also known as: G6P deficiency type IB · G6P translocase deficiency · G6PT deficiency · glucose-6-phosphate transport defect · glycogen storage disease due to G6P deficiency type IB · glycogen storage disease Ib · glycogen storage disease Ic · glycogen storage disease type 1b · glycogen storage disease type I non-a · glycogen storage disease type IB · glycogen storage disease type Ic · glycogenosis due to glucose-6-phosphatase deficiency type 1B · glycogenosis due to glucose-6-phosphatase transport defect type IB · glycogenosis type 1b · glycogenosis type IB · GSD due to G6P deficiency type IB · GSD due to G6PT deficiency · GSD Ib · GSD type 1 non a · GSD type 1b (+4 more)

Data availability: 1,027 ClinVar variants · 6 GenCC gene-disease records · 18 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › leukocyte disorder › leukopenia › agranulocytosis › neutropenia › constitutional neutropenia › glycogen storage disease Ib

Related subtypes (12): cyclic hematopoiesis, Chediak-Higashi syndrome, Cohen syndrome, Lichtenstein syndrome, Barth syndrome, poikiloderma with neutropenia, Griscelli syndrome type 2, Hermansky-Pudlak syndrome 2, primary immunodeficiency syndrome due to p14 deficiency, neutropenia-monocytopenia-deafness syndrome, severe congenital neutropenia, WHIM syndrome 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

252 likely benign, 210 uncertain significance, 49 pathogenic, 41 likely pathogenic, 19 pathogenic/likely pathogenic, 17 conflicting classifications of pathogenicity, 9 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067349	NM_001164277.2(SLC37A4):c.248G>A (p.Gly83Glu)	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068726	NC_000011.9:g.(?118899922)(118900089_?)del	SLC37A4	Pathogenic	criteria provided, single submitter
1076442	NM_001164277.2(SLC37A4):c.1178G>A (p.Trp393Ter)	SLC37A4	Pathogenic	criteria provided, single submitter
1076502	NM_001164277.2(SLC37A4):c.925del (p.Ala309fs)	SLC37A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1076732	NM_001164277.2(SLC37A4):c.494G>A (p.Trp165Ter)	SLC37A4	Pathogenic	criteria provided, single submitter
1184845	NM_001164277.2(SLC37A4):c.1267C>T (p.Arg423Ter)	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1192881	NM_001164277.2(SLC37A4):c.786-3_787del	SLC37A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1301338	NM_001164277.2(SLC37A4):c.1124+3_1124+6del	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356284	NM_001164277.2(SLC37A4):c.340C>T (p.Gln114Ter)	SLC37A4	Pathogenic	criteria provided, single submitter
1364508	NM_001164277.2(SLC37A4):c.71_74dup (p.Tyr25Ter)	SLC37A4	Pathogenic	criteria provided, single submitter
1426093	NM_001164277.2(SLC37A4):c.11del (p.Gln4fs)	SLC37A4	Pathogenic	criteria provided, single submitter
1444451	NM_001164277.2(SLC37A4):c.981del (p.Lys328fs)	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451212	NM_001164277.2(SLC37A4):c.976dup (p.Ser326fs)	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453193	NM_001164277.2(SLC37A4):c.398dup (p.Phe134fs)	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454012	NM_001164277.2(SLC37A4):c.335dup (p.Ala113fs)	SLC37A4	Pathogenic	criteria provided, single submitter
1454284	NM_001164277.2(SLC37A4):c.528_530del (p.Cys176_Val177delinsTrp)	SLC37A4	Pathogenic	criteria provided, single submitter
1460441	NM_001164277.2(SLC37A4):c.1049_1052del (p.Gly350fs)	SLC37A4	Pathogenic	criteria provided, single submitter
1514493	NM_001164277.2(SLC37A4):c.1124+1G>T	SLC37A4	Pathogenic	criteria provided, multiple submitters, no conflicts
188762	NM_001164277.2(SLC37A4):c.742C>T (p.Gln248Ter)	SLC37A4	Pathogenic	criteria provided, multiple submitters, no conflicts
189028	NM_001164277.2(SLC37A4):c.381+1G>A	SLC37A4	Pathogenic	criteria provided, single submitter
189147	NM_001164277.2(SLC37A4):c.652C>T (p.Gln218Ter)	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189162	NM_001164277.2(SLC37A4):c.1A>G (p.Met1Val)	SLC37A4	Pathogenic	criteria provided, single submitter
2011304	NM_001164277.2(SLC37A4):c.778del (p.Leu260_Val261insTer)	SLC37A4	Pathogenic	criteria provided, single submitter
2073022	NM_001164277.2(SLC37A4):c.593del (p.Asn198fs)	SLC37A4	Pathogenic	criteria provided, single submitter
2103538	NM_001164277.2(SLC37A4):c.751dup (p.Leu251fs)	SLC37A4	Pathogenic	criteria provided, single submitter
2104175	NM_001164277.2(SLC37A4):c.962_963del (p.Thr321fs)	SLC37A4	Pathogenic	criteria provided, single submitter
2107823	NM_001164277.2(SLC37A4):c.686del (p.Leu229fs)	SLC37A4	Pathogenic	criteria provided, single submitter
2113017	NM_001164277.2(SLC37A4):c.1028_1036delinsTGCCTCG (p.Tyr343fs)	SLC37A4	Pathogenic	criteria provided, single submitter
2125836	NM_001164277.2(SLC37A4):c.935_936del (p.Thr312fs)	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678945	NM_001164277.2(SLC37A4):c.484_485del (p.Ser162fs)	SLC37A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC37A4	Definitive	Autosomal recessive	glycogen storage disease type 1 due to SLC37A4 mutation	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC37A4	Orphanet:79259	Glycogen storage disease due to glucose-6-phosphatase deficiency type Ib
DPAGT1	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
DPAGT1	Orphanet:86309	DPAGT1-CDG
ARCN1	Orphanet:659702	Intrauterine growth retardation-micrognathia-short stature-facial dysmorphism-rhizomelic shortening syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC37A4	HGNC:4061	ENSG00000137700	O43826	Glucose-6-phosphate exchanger SLC37A4	gencc,clinvar
DPAGT1	HGNC:2995	ENSG00000172269	Q9H3H5	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase	clinvar
ARCN1	HGNC:649	ENSG00000095139	P48444	Coatomer subunit delta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC37A4	Glucose-6-phosphate exchanger SLC37A4	Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum.
DPAGT1	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase	UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
ARCN1	Coatomer subunit delta	Component of the coatomer, a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to t…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	25.9×	0.114
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC37A4	Transporter	yes		Sugar_P_transporter, MFS, MFS_dom
DPAGT1	Enzyme (other)	yes	2.7.8.15	Glycosyl_transferase_4, GPT, DPAGT1_ins
ARCN1	Other/Unknown	no		Longin-like_dom_sf, AP_mu_sigma_su, Coatomer_dsu

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	2
duodenum	1
liver	1
right lobe of liver	1
mucosa of transverse colon	1
right adrenal gland	1
islet of Langerhans	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC37A4	134	ubiquitous	marker	right lobe of liver, liver, duodenum
DPAGT1	271	ubiquitous	marker	mucosa of transverse colon, body of pancreas, right adrenal gland
ARCN1	299	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, body of pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARCN1	3,064
DPAGT1	1,928
SLC37A4	1,242

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC37A4	O43826	25
DPAGT1	Q9H3H5	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARCN1	P48444	84.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective DPAGT1 causes CDG-1j, CMSTA2	1	2855.0×	0.001	DPAGT1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.018	DPAGT1
COPI-dependent Golgi-to-ER retrograde traffic	1	55.4×	0.018	ARCN1
COPI-mediated anterograde transport	1	54.9×	0.018	ARCN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cerebellar Purkinje cell layer maturation	1	2808.7×	0.005	ARCN1
glucose-6-phosphate transport	1	936.2×	0.007	SLC37A4
Golgi localization	1	702.2×	0.007	ARCN1
phosphate ion transmembrane transport	1	401.2×	0.009	SLC37A4
dolichol-linked oligosaccharide biosynthetic process	1	280.9×	0.010	DPAGT1
pigmentation	1	234.1×	0.010	ARCN1
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	112.3×	0.015	ARCN1
gluconeogenesis	1	108.0×	0.015	SLC37A4
adult locomotory behavior	1	100.3×	0.015	ARCN1
protein N-linked glycosylation	1	87.8×	0.015	DPAGT1
glucose metabolic process	1	85.1×	0.015	SLC37A4
endoplasmic reticulum to Golgi vesicle-mediated transport	1	45.3×	0.025	ARCN1
glucose homeostasis	1	43.5×	0.025	SLC37A4
intracellular protein transport	1	21.6×	0.046	ARCN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC37A4	0	0
DPAGT1	0	0
ARCN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DPAGT1	7	Binding:7
SLC37A4	5	Binding:5
ARCN1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DPAGT1	2.7.8.15	UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	SLC37A4, DPAGT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARCN1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC37A4	5	—
DPAGT1	7	—
ARCN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05960617	PHASE2	UNKNOWN	Efficacy and Safety of Empagliflozin in GSD-Ib Patients
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT07459582	Not specified	RECRUITING	Accuracy of Home Lactate Meter and Accu-chek Glucometer in Patients With Glycogen Storage Disease
NCT02054832	Not specified	COMPLETED	Sleep and Quality of Life in Patients With Glycogen Storage Disease on Standard Versus Modified Uncooked Cornstarch
NCT04986735	Not specified	UNKNOWN	Prospective Cohort Study of Children With GSD1b Receiving Empagliflozin
NCT05915910	Not specified	TERMINATED	Prospective Collection of Biospecimen in Pediatric Patients and Adult Guardians Diagnosed With Glycogen Storage Disease Type 1B (GSD1b)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMPAGLIFLOZIN	4	2
LACTIC ACID	4	1
D-LACTIC ACID	3	1