Disorder of glycogen metabolism

disease

On this page

Also known as glycogen storage diseaseglycogen storage disorderglycogenosesglycogenosisGSDinborn error of glycogen metabolic processinborn glycogen metabolic process disorderinborn glycogen storage disorderrare inborn error of glycogen metabolic process

Summary

Disorder of glycogen metabolism (MONDO:0002412) is a disease (an umbrella term covering 24 Mondo subtypes) with 17 cohort genes and 31 clinical trials. The dominant Reactome pathway is Glycogen breakdown (glycogenolysis) (8 cohort genes). Top therapeutic interventions include alglucosidase alfa, avalglucosidase alfa, and cipaglucosidase alfa.

At a glance

Prevalence: 1-9 / 100 000 (China) [Orphanet-validated]
Umbrella term: 24 Mondo subtypes
Cohort genes: 17
ClinVar variants: 56
Clinical trials: 31

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.51	China	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	disorder of glycogen metabolism
Mondo ID	MONDO:0002412
MeSH	D006008
OMIM	232200
Orphanet	79201
DOID	DOID:0050728, DOID:2747
ICD-10-CM	E74.0
ICD-11	1187107383
NCIT	C61272
SNOMED CT	29633007
UMLS	C0017919
MedGen	6639
GARD	0018973
MedDRA	10061990
Is cancer (heuristic)	no

Also known as: glycogen storage disease · glycogen storage disorder · glycogenoses · glycogenosis · GSD · inborn error of glycogen metabolic process · inborn glycogen metabolic process disorder · inborn glycogen storage disorder · rare inborn error of glycogen metabolic process

Data availability: 56 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 24 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism

Related subtypes (17): GLUT1 deficiency syndrome, primary hyperoxaluria, G6PD deficiency, hyperinsulinemic hypoglycemia, multiple carboxylase deficiency, disorder of glycolysis, disorder of fructose metabolism, disorder of galactose metabolism, disorder of carbohydrate transmembrane transport and absorption, disorders of pentose/polyol metabolism, pyruvate dehydrogenase deficiency, disorder of gluconeogenesis, mucopolysaccharidosis, oligosaccharidosis, lactose intolerance, congenital disorder of deglycosylation 1, disorder of galactose and fructose metabolism

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

56 retrieved; paginated sample, class counts are floors:

27 pathogenic, 16 pathogenic/likely pathogenic, 6 likely pathogenic, 4 uncertain significance, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1095	NM_000642.3(AGL):c.16C>T (p.Gln6Ter)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1099	NM_000642.3(AGL):c.4260-12A>G	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195097	NM_000642.3(AGL):c.18_19del (p.Gln6fs)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370565	NM_000642.3(AGL):c.293+1del	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370894	NM_000642.3(AGL):c.3554del (p.Thr1185fs)	AGL	Pathogenic	criteria provided, multiple submitters, no conflicts
456508	NM_000642.3(AGL):c.4459C>T (p.Arg1487Ter)	AGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
973525	NM_000642.3(AGL):c.1497_1500dup (p.Asp501fs)	AGL	Pathogenic	criteria provided, multiple submitters, no conflicts
469	NM_000035.4(ALDOB):c.1005C>G (p.Asn335Lys)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
472	NM_000035.4(ALDOB):c.178C>T (p.Arg60Ter)	ALDOB	Pathogenic	criteria provided, multiple submitters, no conflicts
92483	NM_000152.5(GAA):c.307T>G (p.Cys103Gly)	CCDC40	Pathogenic	reviewed by expert panel
11998	NM_000151.4(G6PC1):c.247C>T (p.Arg83Cys)	G6PC1	Pathogenic	criteria provided, multiple submitters, no conflicts
12000	NM_000151.4(G6PC1):c.1039C>T (p.Gln347Ter)	G6PC1	Pathogenic	criteria provided, multiple submitters, no conflicts
12008	NM_000151.4(G6PC1):c.562G>C (p.Gly188Arg)	G6PC1	Pathogenic	criteria provided, multiple submitters, no conflicts
21062	NM_000151.4(G6PC1):c.79del (p.Gln27fs)	G6PC1	Pathogenic	criteria provided, multiple submitters, no conflicts
214465	NM_000151.4(G6PC1):c.562G>A (p.Gly188Ser)	G6PC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188936	NM_000152.5(GAA):c.1827del (p.Arg608_Tyr609insTer)	GAA	Pathogenic	reviewed by expert panel
189144	NM_000152.5(GAA):c.1826dup (p.Tyr609Ter)	GAA	Pathogenic	reviewed by expert panel
265160	NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)	GAA	Pathogenic	reviewed by expert panel
280955	NM_000152.5(GAA):c.546G>A (p.Thr182=)	GAA	Pathogenic	reviewed by expert panel
3637873	NM_000152.5(GAA):c.1626del (p.Tyr543fs)	GAA	Pathogenic	criteria provided, multiple submitters, no conflicts
371305	NM_000152.5(GAA):c.1316T>A (p.Met439Lys)	GAA	Pathogenic	reviewed by expert panel
4027	NM_000152.5(GAA):c.-32-13T>G	GAA	Pathogenic	reviewed by expert panel
4033	NM_000152.5(GAA):c.525del (p.Glu176fs)	GAA	Pathogenic	reviewed by expert panel
596146	NM_000152.5(GAA):c.482_483del (p.Pro161fs)	GAA	Pathogenic	reviewed by expert panel
92480	NM_000152.5(GAA):c.2544del (p.Lys849fs)	GAA	Pathogenic	reviewed by expert panel
932903	NM_000152.5(GAA):c.722_723del (p.Phe241fs)	GAA	Pathogenic	reviewed by expert panel
208584	NM_000158.4(GBE1):c.691+2T>C	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2777	NM_000158.4(GBE1):c.986A>C (p.Tyr329Ser)	GBE1	Pathogenic	criteria provided, multiple submitters, no conflicts
2790	NM_000158.4(GBE1):c.708G>C (p.Gln236His)	GBE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162663	NM_004130.4(GYG1):c.304G>C (p.Asp102His)	GYG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 26 · 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
PYGM	Strong	Autosomal recessive	glycogen storage disease V	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PYGM	Orphanet:368	Glycogen storage disease due to muscle glycogen phosphorylase deficiency
CCDC40	Orphanet:244	Primary ciliary dyskinesia
AGL	Orphanet:366	Glycogen storage disease due to glycogen debranching enzyme deficiency
FBP1	Orphanet:348	Fructose-1,6-bisphosphatase deficiency
G6PC1	Orphanet:79258	Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia
SLC37A4	Orphanet:79259	Glycogen storage disease due to glucose-6-phosphatase deficiency type Ib
GAA	Orphanet:308552	Glycogen storage disease due to acid maltase deficiency, infantile onset
GAA	Orphanet:420429	Glycogen storage disease due to acid maltase deficiency, late-onset
ALDOB	Orphanet:469	Hereditary fructose intolerance
GBE1	Orphanet:206583	Adult polyglucosan body disease
GBE1	Orphanet:308621	Glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form
GBE1	Orphanet:308638	Glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form
GBE1	Orphanet:308655	Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form
GBE1	Orphanet:308670	Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form
GBE1	Orphanet:308684	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form
GBE1	Orphanet:308698	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form
GBE1	Orphanet:308712	Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form
GYG1	Orphanet:263297	Glycogen storage disease with severe cardiomyopathy due to glycogenin deficiency
GYG1	Orphanet:456369	Polyglucosan body myopathy type 2
GYS1	Orphanet:137625	Glycogen storage disease due to muscle and heart glycogen synthase deficiency
GYS2	Orphanet:2089	Glycogen storage disease due to hepatic glycogen synthase deficiency
PFKM	Orphanet:371	Glycogen storage disease due to muscle phosphofructokinase deficiency
PHKA1	Orphanet:715	Glycogen storage disease due to muscle phosphorylase kinase deficiency
PHKA2	Orphanet:264580	Glycogen storage disease due to liver phosphorylase kinase deficiency
PHKB	Orphanet:79240	Glycogen storage disease due to liver and muscle phosphorylase kinase deficiency
PYGL	Orphanet:369	Glycogen storage disease due to liver glycogen phosphorylase deficiency

Cohort genes → proteins

17 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PYGM	HGNC:9726	ENSG00000068976	P11217	Glycogen phosphorylase, muscle form	gencc,clinvar
CCDC40	HGNC:26090	ENSG00000141519	Q4G0X9	Coiled-coil domain-containing protein 40	clinvar
AGL	HGNC:321	ENSG00000162688	P35573	Glycogen debranching enzyme	clinvar
FBP1	HGNC:3606	ENSG00000165140	P09467	Fructose-1,6-bisphosphatase 1	clinvar
G6PC1	HGNC:4056	ENSG00000131482	P35575	Glucose-6-phosphatase catalytic subunit 1	clinvar
SLC37A4	HGNC:4061	ENSG00000137700	O43826	Glucose-6-phosphate exchanger SLC37A4	clinvar
GAA	HGNC:4065	ENSG00000171298	P10253	Lysosomal alpha-glucosidase	clinvar
ALDOB	HGNC:417	ENSG00000136872	P05062	Fructose-bisphosphate aldolase B	clinvar
GBE1	HGNC:4180	ENSG00000114480	Q04446	1,4-alpha-glucan-branching enzyme	clinvar
GYG1	HGNC:4699	ENSG00000163754	P46976	Glycogenin-1	clinvar
GYS1	HGNC:4706	ENSG00000104812	P13807	Glycogen [starch] synthase, muscle	clinvar
GYS2	HGNC:4707	ENSG00000111713	P54840	Glycogen [starch] synthase, liver	clinvar
PFKM	HGNC:8877	ENSG00000152556	P08237	ATP-dependent 6-phosphofructokinase, muscle type	clinvar
PHKA1	HGNC:8925	ENSG00000067177	P46020	Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform	clinvar
PHKA2	HGNC:8926	ENSG00000044446	P46019	Phosphorylase b kinase regulatory subunit alpha, liver isoform	clinvar
PHKB	HGNC:8927	ENSG00000102893	Q93100	Phosphorylase b kinase regulatory subunit beta	clinvar
PYGL	HGNC:9725	ENSG00000100504	P06737	Glycogen phosphorylase, liver form	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PYGM	Glycogen phosphorylase, muscle form	Allosteric enzyme that catalyzes the rate-limiting step in glycogen catabolism, the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, and plays a central role in maintaining cellular and organismal glucose homeostasis.
CCDC40	Coiled-coil domain-containing protein 40	Required for assembly of dynein regulatory complex (DRC) and inner dynein arm (IDA) complexes, which are responsible for ciliary beat regulation, thereby playing a central role in motility in cilia and flagella.
AGL	Glycogen debranching enzyme	Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.
FBP1	Fructose-1,6-bisphosphatase 1	Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations, acting as a rate-limiting enzyme in gluconeogenesis.
G6PC1	Glucose-6-phosphatase catalytic subunit 1	Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum.
SLC37A4	Glucose-6-phosphate exchanger SLC37A4	Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum.
GAA	Lysosomal alpha-glucosidase	Essential for the degradation of glycogen in lysosomes.
ALDOB	Fructose-bisphosphate aldolase B	Catalyzes the aldol cleavage of fructose 1,6-biphosphate to form two triosephosphates dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in glycolysis as well as the reverse stereospecific aldol addition reaction in gluconeogenesi…
GBE1	1,4-alpha-glucan-branching enzyme	Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase.
GYG1	Glycogenin-1	Glycogenin participates in the glycogen biosynthetic process along with glycogen synthase and glycogen branching enzyme.
GYS1	Glycogen [starch] synthase, muscle	Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme.
GYS2	Glycogen [starch] synthase, liver	Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme.
PFKM	ATP-dependent 6-phosphofructokinase, muscle type	Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.
PHKA1	Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.
PHKA2	Phosphorylase b kinase regulatory subunit alpha, liver isoform	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.
PHKB	Phosphorylase b kinase regulatory subunit beta	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.
PYGL	Glycogen phosphorylase, liver form	Allosteric enzyme that catalyzes the rate-limiting step in glycogen catabolism, the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, and plays a central role in maintaining cellular and organismal glucose homeostasis.

Protein-family classification

Druggable: 14 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.82

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
Enzyme (other)	9	6.3×	2e-05
Phosphatase	2	9.9×	0.051
Transporter	1	4.6×	0.395
Antibody/Immunoglobulin	1	1.7×	0.558
Kinase	1	1.6×	0.558
Other/Unknown	3	0.3×	1.000

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PYGM	Other/Unknown	no		Glyco_trans_35, Glycg_phsphrylas, Pyridoxal_P_attach_site
CCDC40	Other/Unknown	no		CCDC40
AGL	Enzyme (other)	yes	3.2.1.33	Glycogen_debranch_met, 6-hairpin_glycosidase_sf, AGL/Gdb1
FBP1	Phosphatase	yes	3.1.3.11	FBPase_class-1, Fructose_bisphosphatase_AS, FBPtase
G6PC1	Phosphatase	yes	3.1.3.9	PAP2/HPO, Glucose-6-phosphatase, PAP2/HPO_sf
SLC37A4	Transporter	yes		Sugar_P_transporter, MFS, MFS_dom
GAA	Enzyme (other)	yes	3.2.1.20	Glyco_hydro_31_TIM, P_trefoil_dom, Gal_mutarotase_sf_dom
ALDOB	Enzyme (other)	yes	4.1.2.13	FBA_I, Aldolase_TIM, Aldolase_I_AS
GBE1	Antibody/Immunoglobulin	yes		Glyco_hydro_13_N, GH13_cat_dom, A-amylase/branching_C
GYG1	Enzyme (other)	yes	2.4.1.186	Glyco_trans_8, Nucleotide-diphossugar_trans, GNT1/Glycosyltrans_8
GYS1	Enzyme (other)	yes	2.4.1.11	Glycogen_synth
GYS2	Other/Unknown	no		Glycogen_synth
PFKM	Kinase	yes	2.7.1.11	Phosphofructokinase_dom, 6-Pfructokinase_euk, Phosphofructokinase_CS
PHKA1	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like
PHKA2	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like
PHKB	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like
PYGL	Enzyme (other)	yes	2.4.1.1	Glyco_trans_35, Glycg_phsphrylas, Pyridoxal_P_attach_site

Expression context

Cohort genes with no expression data: 0.

16 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	6
biceps brachii	4
gastrocnemius	3
skeletal muscle tissue of rectus abdominis	3
liver	3
gluteal muscle	3
hindlimb stylopod muscle	2
right uterine tube	2
vastus lateralis	2
jejunal mucosa	2
nephron tubule	2
apex of heart	2
skeletal muscle tissue of biceps brachii	1
bronchial epithelial cell	1
sural nerve	1
endometrium epithelium	1
duodenum	1
granulocyte	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PYGM	227	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, gastrocnemius
CCDC40	184	ubiquitous	marker	right uterine tube, bronchial epithelial cell, sural nerve
AGL	294	ubiquitous	marker	vastus lateralis, biceps brachii, skeletal muscle tissue of rectus abdominis
FBP1	213	broad	marker	right lobe of liver, endometrium epithelium, jejunal mucosa
G6PC1	66	tissue_specific	marker	right lobe of liver, liver, nephron tubule
SLC37A4	134	ubiquitous	marker	right lobe of liver, liver, duodenum
GAA	261	ubiquitous	marker	granulocyte, left testis, right testis
ALDOB	191	tissue_specific	marker	jejunal mucosa, nephron tubule, right lobe of liver
GBE1	293	ubiquitous	marker	gluteal muscle, tibialis anterior, biceps brachii
GYG1	304	ubiquitous	marker	biceps brachii, deltoid, gluteal muscle
GYS1	257	ubiquitous	marker	hindlimb stylopod muscle, apex of heart, gastrocnemius
GYS2	51	tissue_specific	yes	right lobe of liver, liver, primordial germ cell in gonad
PFKM	302	ubiquitous	marker	gluteal muscle, triceps brachii, skeletal muscle tissue of rectus abdominis
PHKA1	227	ubiquitous	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, biceps brachii
PHKA2	266	ubiquitous	marker	right lobe of liver, right uterine tube, apex of heart
PHKB	299	ubiquitous	marker	adrenal tissue, vastus lateralis, quadriceps femoris
PYGL	255	ubiquitous	marker	blood, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 59.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PFKM	3,710
GBE1	3,402
FBP1	3,376
GYS1	2,900
PYGL	2,733
PYGM	2,565
GYS2	2,307
G6PC1	2,193
GAA	2,116
ALDOB	2,036

Intra-cohort edges

A	B	Sources
AGL	G6PC1	string_interaction
AGL	GAA	string_interaction
AGL	GBE1	string_interaction
AGL	GYG1	string_interaction
AGL	GYS1	string_interaction
AGL	GYS2	string_interaction
AGL	PHKA1	string_interaction
AGL	PHKA2	string_interaction
AGL	PHKB	string_interaction
AGL	PYGL	string_interaction
AGL	PYGM	string_interaction
AGL	SLC37A4	string_interaction
ALDOB	FBP1	string_interaction
ALDOB	PFKM	string_interaction
FBP1	G6PC1	string_interaction
FBP1	PFKM	string_interaction
G6PC1	GYS2	string_interaction
G6PC1	PFKM	string_interaction
G6PC1	PYGL	string_interaction
G6PC1	PYGM	string_interaction
G6PC1	SLC37A4	string_interaction
GAA	GBE1	string_interaction
GAA	GYG1	string_interaction
GAA	PYGL	string_interaction
GAA	PYGM	string_interaction
GBE1	GYG1	biogrid_interaction, intact, string_interaction
GBE1	GYS1	biogrid_interaction, intact, string_interaction
GBE1	GYS2	string_interaction
GBE1	PHKA1	string_interaction
GBE1	PHKA2	string_interaction
GBE1	PHKB	string_interaction
GBE1	PYGL	biogrid_interaction, string_interaction
GBE1	PYGM	biogrid_interaction, string_interaction
GBE1	SLC37A4	string_interaction
GYG1	GYS1	biogrid_interaction, intact, string_interaction
GYG1	GYS2	string_interaction
GYG1	PYGL	string_interaction
GYG1	PYGM	string_interaction
GYS1	PHKA1	string_interaction
GYS1	PYGL	string_interaction
GYS1	PYGM	string_interaction
GYS2	PHKA2	string_interaction
GYS2	PHKB	string_interaction
GYS2	PYGL	string_interaction
GYS2	PYGM	string_interaction
GYS2	SLC37A4	string_interaction
PFKM	PHKA2	string_interaction
PHKA1	PHKA2	intact
PHKA1	PHKB	string_interaction
PHKA1	PYGL	string_interaction

Structural data

PDB: 15 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBP1	P09467	51
SLC37A4	O43826	25
GYG1	P46976	23
GAA	P10253	19
PYGL	P06737	19
PHKA1	P46020	10
GYS1	P13807	9
G6PC1	P35575	6
PHKB	Q93100	6
ALDOB	P05062	4
GBE1	Q04446	3
PYGM	P11217	1
CCDC40	Q4G0X9	1
AGL	P35573	1
PFKM	P08237	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GYS2	P54840	87.08
PHKA2	P46019	81.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 17 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycogen breakdown (glycogenolysis)	8	406.0×	2e-19	PYGM, AGL, GAA, GYG1, PHKA1, PHKA2, PHKB, PYGL
Glycogen metabolism	4	507.6×	4e-10	GAA, PHKA1, PHKA2, PHKB
Glycogen synthesis	4	217.5×	2e-08	GBE1, GYG1, GYS1, GYS2
Metabolism of carbohydrates and carbohydrate derivatives	5	40.1×	7e-07	GAA, ALDOB, PHKA1, PHKA2, PHKB
Glycogen storage disease type XV (GYG1)	2	761.3×	6e-06	GYG1, GYS1
Glycogen storage disease type 0 (muscle GYS1)	2	761.3×	6e-06	GYG1, GYS1
Glycogen storage disease type II (GAA)	2	761.3×	6e-06	GAA, GYG1
Glycogen storage disease type IV (GBE1)	2	507.6×	1e-05	GBE1, GYS2
Gluconeogenesis	3	87.8×	1e-05	FBP1, G6PC1, ALDOB
Myoclonic epilepsy of Lafora	2	169.2×	2e-04	GYG1, GYS1
Diseases of carbohydrate metabolism	2	108.8×	4e-04	GAA, ALDOB
Glycogen storage disease type Ia (G6PC)	1	761.3×	0.003	G6PC1
Hereditary fructose intolerance	1	761.3×	0.003	ALDOB
Glycolysis	2	38.1×	0.003	ALDOB, PFKM
Glycogen storage diseases	1	380.7×	0.004	GAA
Glycogen storage disease type 0 (liver GYS2)	1	380.7×	0.004	GYS2
Neutrophil degranulation	4	6.2×	0.005	AGL, GAA, GYG1, PYGL
Fructose metabolism	1	152.3×	0.009	ALDOB
Fructose catabolism	1	152.3×	0.009	ALDOB
Interaction of NuRD complexes with transcription factors	2	16.9×	0.009	FBP1, G6PC1
Metabolism	5	3.9×	0.009	GAA, ALDOB, PHKA1, PHKA2, PHKB
Diseases of metabolism	2	10.7×	0.018	GAA, ALDOB
Glucose metabolism	1	58.6×	0.020	ALDOB
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	25.4×	0.044	G6PC1
Disease	2	1.7×	0.346	GAA, ALDOB
Innate Immune System	1	1.7×	0.469	GAA
Immune System	1	0.9×	0.700	GAA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycogen catabolic process	6	424.8×	5e-14	PYGM, AGL, G6PC1, GAA, PFKM, PYGL
glycogen metabolic process	7	216.8×	5e-14	PYGM, G6PC1, GBE1, PHKA1, PHKA2, PHKB, PYGL
glycogen biosynthetic process	5	275.4×	1e-10	AGL, GBE1, GYG1, GYS1, GYS2
fructose 1,6-bisphosphate metabolic process	3	371.7×	1e-06	FBP1, ALDOB, PFKM
generation of precursor metabolites and energy	4	80.9×	3e-06	GBE1, PHKA1, PHKA2, PHKB
gluconeogenesis	4	76.2×	3e-06	FBP1, G6PC1, SLC37A4, ALDOB
glucose homeostasis	4	30.7×	9e-05	G6PC1, SLC37A4, PFKM, PYGL
glucose-6-phosphate transport	2	330.4×	2e-04	G6PC1, SLC37A4
fructose metabolic process	2	198.3×	4e-04	FBP1, ALDOB
fructose 6-phosphate metabolic process	2	132.2×	9e-04	FBP1, PFKM
muscle cell cellular homeostasis	2	76.2×	0.002	GAA, PFKM
maltose metabolic process	1	991.3×	0.005	GAA
sucrose metabolic process	1	991.3×	0.005	GAA
obsolete vacuolar sequestering	1	991.3×	0.005	GAA
glycolytic process through fructose-6-phosphate	1	991.3×	0.005	PFKM
glycolysis from storage polysaccharide through glucose-1-phosphate	1	991.3×	0.005	PFKM
obsolete glycogen biosynthetic process via UDP-glucose	1	991.3×	0.005	GYG1
glycolytic process	2	45.1×	0.005	ALDOB, PFKM
negative regulation of pentose-phosphate shunt	1	495.6×	0.009	ALDOB
glucose metabolic process	2	30.0×	0.009	SLC37A4, GAA
obsolete fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate	1	330.4×	0.012	ALDOB
cellular hypotonic salinity response	1	330.4×	0.012	FBP1
cellular response to raffinose	1	330.4×	0.012	FBP1
diaphragm contraction	1	247.8×	0.014	GAA
positive regulation of glycogen catabolic process	1	247.8×	0.014	PHKA1
cellular response to insulin stimulus	2	20.0×	0.015	FBP1, G6PC1
determination of pancreatic left/right asymmetry	1	198.3×	0.016	CCDC40
response to resveratrol	1	198.3×	0.016	G6PC1
vacuolar proton-transporting V-type ATPase complex assembly	1	165.2×	0.017	ALDOB
cellular hyperosmotic salinity response	1	165.2×	0.017	FBP1

Therapeutics

Drugs indicated for this disease

0 approved, 3 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Alglucosidase Alfa	Phase 3 (in late-stage trials)
Cipaglucosidase Alfa	Phase 3 (in late-stage trials)
Miglustat	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Avalglucosidase Alfa.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 12

Druggability breadth: 12 of 17 evidence-associated genes (71%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
AGL	MIGLUSTAT
FBP1	ADENOSINE PHOSPHATE
GAA	DIENESTROL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GAA	112	4
FBP1	5	4
AGL	4	4
PYGL	3	3
PYGM	1	3
CCDC40	0	0
G6PC1	0	0
SLC37A4	0	0
ALDOB	0	0
GBE1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGLUSTAT	4	AGL, GAA
MIGALASTAT	4	AGL, GAA
ADENOSINE PHOSPHATE	4	FBP1
DISULFIRAM	4	FBP1
DIENESTROL	4	GAA
DICLOFENAC SODIUM	4	GAA
DIBUCAINE	4	GAA
AMLEXANOX	4	GAA
ARIPIPRAZOLE	4	GAA
DULOXETINE	4	GAA
LABETALOL HYDROCHLORIDE	4	GAA
MORICIZINE HYDROCHLORIDE	4	GAA
PHENYLEPHRINE HYDROCHLORIDE	4	GAA
DEMECLOCYCLINE HYDROCHLORIDE	4	GAA
DOXAZOSIN MESYLATE	4	GAA
PRILOCAINE HYDROCHLORIDE	4	GAA
FLUOROMETHOLONE	4	GAA
PHENELZINE SULFATE	4	GAA
RABEPRAZOLE SODIUM	4	GAA
METHYSERGIDE MALEATE	4	GAA
ACRISORCIN	4	GAA
ECONAZOLE NITRATE	4	GAA
ISOETHARINE MESYLATE	4	GAA
QUINESTROL	4	GAA
DEFEROXAMINE MESYLATE	4	GAA
MAPROTILINE HYDROCHLORIDE	4	GAA
EPINEPHRINE BITARTRATE	4	GAA
PROCHLORPERAZINE MALEATE	4	GAA
IRBESARTAN	4	GAA
OXYTETRACYCLINE	4	GAA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 12.

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

Symbol	Assays	Type breakdown
GAA	280	Binding:267, Functional:13
FBP1	125	Binding:125
PYGL	58	Binding:58
PHKA2	48	Binding:48
PHKB	21	Binding:21
PHKA1	20	Binding:20
PYGM	18	Binding:18
GYS1	15	Binding:15
G6PC1	8	Binding:8
SLC37A4	5	Binding:5
AGL	4	Binding:4
GYS2	2	Binding:2
PFKM	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGL	3.2.1.33	amylo-alpha-1,6-glucosidase
FBP1	3.1.3.11	fructose-bisphosphatase
G6PC1	3.1.3.9	glucose-6-phosphatase
GAA	3.2.1.20	alpha-glucosidase
ALDOB	4.1.2.13	fructose-bisphosphate aldolase
GYG1	2.4.1.186	glycogenin glucosyltransferase
GYS1	2.4.1.11	glycogen(starch) synthase
PFKM	2.7.1.11	6-phosphofructokinase
PHKA1	2.7.11.19	phosphorylase kinase
PHKA2	2.7.11.19	phosphorylase kinase
PHKB	2.7.11.19	phosphorylase kinase
PYGL	2.4.1.1	glycogen phosphorylase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FBP1	125
GAA	280

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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.

Compound	Max phase	Cohort target (bioactivity)
MIGALASTAT	4	AGL, GAA
ADENOSINE PHOSPHATE	4	FBP1
DISULFIRAM	4	FBP1
DIENESTROL	4	GAA
DICLOFENAC SODIUM	4	GAA
DIBUCAINE	4	GAA
AMLEXANOX	4	GAA
ARIPIPRAZOLE	4	GAA
DULOXETINE	4	GAA
LABETALOL HYDROCHLORIDE	4	GAA
MORICIZINE HYDROCHLORIDE	4	GAA
PHENYLEPHRINE HYDROCHLORIDE	4	GAA
DEMECLOCYCLINE HYDROCHLORIDE	4	GAA
DOXAZOSIN MESYLATE	4	GAA
PRILOCAINE HYDROCHLORIDE	4	GAA
FLUOROMETHOLONE	4	GAA
PHENELZINE SULFATE	4	GAA
RABEPRAZOLE SODIUM	4	GAA
METHYSERGIDE MALEATE	4	GAA
ACRISORCIN	4	GAA
ECONAZOLE NITRATE	4	GAA
ISOETHARINE MESYLATE	4	GAA
QUINESTROL	4	GAA
DEFEROXAMINE MESYLATE	4	GAA
MAPROTILINE HYDROCHLORIDE	4	GAA
EPINEPHRINE BITARTRATE	4	GAA
PROCHLORPERAZINE MALEATE	4	GAA
IRBESARTAN	4	GAA
OXYTETRACYCLINE	4	GAA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	AGL, FBP1, GAA
B	Phased (≥1) drug, not yet approved	2	PYGM, PYGL
C	Druggable family + PDB, no drug	9	G6PC1, SLC37A4, ALDOB, GBE1, GYG1, GYS1, PFKM, PHKA1, PHKB
D	Druggable family + AlphaFold only, no drug	1	PHKA2
E	Difficult family or no structure, no drug	2	CCDC40, GYS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GBE1	0	AGL, PYGL
GYS1	15	AGL
GYS2	2	PYGL, PYGM
PHKB	21	PYGM, PYGL
CCDC40	0	—
G6PC1	8	—
SLC37A4	5	—
ALDOB	0	—
GYG1	0	—
PFKM	2	—
PHKA1	20	—
PHKA2	48	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	24
PHASE2	4
PHASE3	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04808505	PHASE3	RECRUITING	A Study to Evaluate the Safety, Efficacy, PK, PD and Immunogenicity of Cipaglucosidase Alfa/Miglustat in IOPD Subjects Aged 0 to <18
NCT02782741	PHASE3	COMPLETED	Study to Compare the Efficacy and Safety of Enzyme Replacement Therapies Avalglucosidase Alfa and Alglucosidase Alfa Administered Every Other Week in Patients With Late-onset Pompe Disease Who Have Not Been Previously Treated for Pompe Disease
NCT03019406	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Assess Safety and Efficacy of Avalglucosidase Alfa Administered Every Other Week in Pediatric Patients With Infantile-onset Pompe Disease Previously Treated With Alglucosidase Alfa
NCT05095727	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of mRNA-3745 in Adult and Pediatric Participants With Glycogen Storage Disease Type 1a (GSD1a)
NCT00765414	PHASE2	COMPLETED	Extension Study of Long-term Safety and Efficacy of Myozyme for a Single Patient With Pompe Disease Who Were Previously Enrolled in Genzyme Sponsored ERT Studies.
NCT02032524	PHASE2	COMPLETED	Avalglucosidase Alfa Extension Study
NCT06130228	PHASE2	UNKNOWN	Nutritional Therapy in Late-onset Pompe Disease
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03564561	Not specified	RECRUITING	Natural History of Pompe Disease
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04929002	Not specified	ACTIVE_NOT_RECRUITING	Carbon-13 Magnetic Resonance Spectroscopy in Glycogen Storage Diseases
NCT06396546	Not specified	RECRUITING	‘Glycogen Storage Diseases (GSDs) in Indian Children- Establishing an Indian GSD (I-GSD) Registry’
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study
NCT06813443	Not specified	RECRUITING	Characterization of Patients With Cardiomyopathy to Identify Critical Patients Candidates for Cardiac Transplantation
NCT07136844	Not specified	RECRUITING	Gait Analysis Parameter and Upper Limb Evaluation in Adult Patients With Neurological or Metabolic Pathology
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques
NCT00001342	Not specified	COMPLETED	Study of Glycogen Storage Disease and Associated Disorders
NCT00566878	Not specified	COMPLETED	Pompe Lactation Sub-Registry
NCT01461304	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism
NCT02057731	Not specified	COMPLETED	Study of Glycogen Storage Disease Expression in Carriers
NCT02176096	Not specified	COMPLETED	Comparison of the Effect of a Novel Starch (Glycosade) Versus Gastrostomy Tube-Dextrose Infusion on Overnight Euglycaemia Control in Children With Glycogen Storage Disease Type I: Open Label Demonstration Trial
NCT02318966	Not specified	COMPLETED	Glycosade v UCCS in the Dietary Management of Hepatic GSD
NCT02338817	Not specified	TERMINATED	Clinical Evaluation of a Non-Invasive Hypoglycemia Detector in a Glycogen Storage Disease Population
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT03255213	Not specified	COMPLETED	Lingual Muscle Training in Late-Onset Pompe Disease (LOPD)
NCT04292938	Not specified	COMPLETED	McArdle Disease Treatment by Ketogenic Diet
NCT04399694	Not specified	COMPLETED	Identification and Characterization of Novel Non-Coding Variants That Contribute to Genetic Disorders
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT07614139	Not specified	COMPLETED	Continuous Glucose Monitoring Alerts, Accuracy, and Patient Outcomes in Adults With Inherited Metabolic Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALGLUCOSIDASE ALFA	4	4
AVALGLUCOSIDASE ALFA	4	3
CIPAGLUCOSIDASE ALFA	4	1
MIGLUSTAT	4	1
TRIHEPTANOIN	4	1

Cohort genes: PYGM, CCDC40, AGL, FBP1, G6PC1, SLC37A4, GAA, ALDOB, GBE1, GYG1, GYS1, GYS2, PFKM, PHKA1, PHKA2, PHKB, PYGL
Drugs: Alglucosidase Alfa, Avalglucosidase Alfa, Cipaglucosidase Alfa, Miglustat, Triheptanoin