glycogen storage disease II

Summary

glycogen storage disease II (MONDO:0009290) is a disease caused by GAA (GenCC Definitive), with 3 cohort genes and 124 clinical trials. Top therapeutic interventions include alglucosidase alfa, cipaglucosidase alfa, and avalglucosidase alfa.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: GAA (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 2,883
• Phenotypes (HPO): 72
• Clinical trials: 124

Clinical features

Epidemiology

Prevalence records

13 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.17	Portugal	Validated
Prevalence at birth	1-9 / 1 000 000	0.83	Italy	Validated
Prevalence at birth	1-9 / 100 000	2.25	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.37	Czech Republic	Validated
Prevalence at birth	1-5 / 10 000	11.5	Austria	Validated
Prevalence at birth	1-9 / 100 000	2.5	United States	Validated
Prevalence at birth	1-9 / 1 000 000	0.68	Australia	Validated
Prevalence at birth	1-9 / 100 000	2	China	Validated
Prevalence at birth	1-9 / 1 000 000	0.72	Sweden	Validated
Prevalence at birth	1-9 / 100 000	2.3	Israel	Validated
Prevalence at birth	1-9 / 100 000	4.8	Specific population	Validated
Prevalence at birth	1-9 / 1 000 000	0.8	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0009073	Progressive proximal muscle weakness	Very frequent (80-99%)
HP:0010471	Oligosacchariduria	Very frequent (80-99%)
HP:0034932	Decreased circulating acid maltase activity	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001308	Tongue fasciculations	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001640	Cardiomegaly	Frequent (30-79%)
HP:0001712	Left ventricular hypertrophy	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0002875	Exertional dyspnea	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0011947	Respiratory tract infection	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0030148	Heart murmur	Frequent (30-79%)
HP:0030231	Glycogen accumulation in muscle fiber lysosomes	Frequent (30-79%)
HP:0031964	Elevated circulating alanine aminotransferase concentration	Frequent (30-79%)
HP:0100595	Camptocormia	Frequent (30-79%)
HP:3000062	Abnormal internal carotid artery morphology	Occasional (5-29%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0000183	Tongue muscle weakness	Occasional (5-29%)
HP:0000297	Facial hypotonia	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002326	Transient ischemic attack	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002633	Vasculitis	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease II
Mondo ID	MONDO:0009290
Orphanet	365
DOID	DOID:2752
ICD-10-CM	E74.02
ICD-11	1427054474
NCIT	C84734
SNOMED CT	274864009
UMLS	C0017921
MedGen	5340
GARD	0005714
MedDRA	10053185
NORD	1595
Is cancer (heuristic)	no

Also known as: acid maltase deficiency · acid maltase deficiency disease · Aglucosidase alfa · Alpha-1,4-glucosidase acid deficiency · deficiency of alpha-glucosidase · deficiency of lysosomal alpha-glucosidase · GAA glycogen storage disease · generalised glycogenosis · glucosidase acid-1,4-alpha deficiency · glycogen storage disease caused by mutation in GAA · glycogen storage disease II · glycogen storage disease type 2 · glycogen storage disease type II · glycogenosis due to acid maltase deficiency · glycogenosis type 2 · glycogenosis type II · GSD due to acid maltase deficiency · GSD II · GSD type 2 · GSD type II (+3 more)

Data availability: 2,883 ClinVar variants · 394 ClinGen variant curations · 6 GenCC gene-disease records · 99 cell lines.

Disease family

An umbrella term covering 2 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 › glycogen storage disease II

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease III, glycogen storage disease due to glycogen branching enzyme deficiency, glycogen storage disease V, glycogen storage disease VI, glycogen storage disease VII, glycogen storage disorder due to hepatic glycogen synthase deficiency, Lafora disease, glycogen storage disease due to phosphoglycerate mutase deficiency, lethal congenital glycogen storage disease of heart, Danon disease, glycogen storage disease IXd, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, glycogen storage disease due to muscle and heart glycogen synthase deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, polyglucosan body myopathy 1 with or without immunodeficiency, glycogen storage disease due to lactate dehydrogenase deficiency, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, glycogen storage disease due to liver phosphorylase kinase deficiency, GYG1-related disorder of glycogen metabolism, glycogen storage disease IX

Subtypes (2): glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease due to acid maltase deficiency, late-onset

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:

298 likely benign, 178 uncertain significance, 56 pathogenic, 23 pathogenic/likely pathogenic, 21 likely pathogenic, 13 conflicting classifications of pathogenicity, 7 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1321358	NM_000152.5(GAA):c.[752C>T;761C>T]		Pathogenic	criteria provided, multiple submitters, no conflicts
1002225	NM_000152.5(GAA):c.1844G>T (p.Gly615Val)	GAA	Pathogenic	criteria provided, single submitter
1065143	NM_000152.5(GAA):c.1551+1G>A	GAA	Pathogenic	reviewed by expert panel
1068509	NM_000152.5(GAA):c.1336dup (p.Ile446fs)	GAA	Pathogenic	criteria provided, single submitter
1068640	NM_000152.5(GAA):c.340_341insT (p.Lys114fs)	GAA	Pathogenic	reviewed by expert panel
1068774	NM_000152.5(GAA):c.1214T>C (p.Leu405Pro)	GAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068980	NM_000152.5(GAA):c.1557_1561dup (p.Glu521fs)	GAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069100	NM_000152.5(GAA):c.1704dup (p.Tyr569fs)	GAA	Pathogenic	criteria provided, single submitter
1070357	NM_000152.5(GAA):c.1987C>T (p.Gln663Ter)	GAA	Pathogenic	criteria provided, single submitter
1070552	NM_000152.5(GAA):c.1134C>A (p.Tyr378Ter)	GAA	Pathogenic	criteria provided, single submitter
1071063	NM_000152.5(GAA):c.2167G>A (p.Val723Met)	GAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072074	NC_000017.10:g.(?78091972)(78092176_?)del	GAA	Pathogenic	criteria provided, single submitter
1072075	NC_000017.10:g.(?_78091652)_78092189del	GAA	Pathogenic	criteria provided, single submitter
1072307	NM_000152.5(GAA):c.1976_1977del (p.Val659fs)	GAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072806	NM_000152.5(GAA):c.683dup (p.Arg229fs)	GAA	Pathogenic	criteria provided, single submitter
1072906	NM_000152.5(GAA):c.1579_1580del (p.Arg527fs)	GAA	Pathogenic	reviewed by expert panel
1073372	NM_000152.5(GAA):c.1443G>A (p.Trp481Ter)	GAA	Pathogenic	criteria provided, multiple submitters, no conflicts
1073996	NM_000152.5(GAA):c.282del (p.Asp95fs)	GAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074160	NM_000152.5(GAA):c.199del (p.Asp67fs)	GAA	Pathogenic	criteria provided, single submitter
1074956	NM_000152.5(GAA):c.2408_2426del (p.Gln803fs)	GAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075601	NM_000152.5(GAA):c.2173del (p.Arg725fs)	GAA	Pathogenic	criteria provided, single submitter
1076447	NM_000152.5(GAA):c.1308del (p.Arg437fs)	GAA	Pathogenic	criteria provided, single submitter
1217288	NM_000152.5(GAA):c.2482-2A>G	GAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322949	NM_000152.5(GAA):c.2261dup (p.Val755fs)	GAA	Pathogenic	reviewed by expert panel
1322950	NM_000152.5(GAA):c.2431dup (p.Leu811fs)	GAA	Pathogenic	reviewed by expert panel
1322953	NM_000152.5(GAA):c.995C>A (p.Ser332Ter)	GAA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322955	NM_000152.5(GAA):c.1846del (p.Asp616fs)	GAA	Pathogenic	criteria provided, multiple submitters, no conflicts
1322956	NM_000152.5(GAA):c.2623C>T (p.Gln875Ter)	GAA	Pathogenic	criteria provided, multiple submitters, no conflicts
1322958	NM_000152.5(GAA):c.2431del (p.Leu811fs)	GAA	Pathogenic	criteria provided, multiple submitters, no conflicts
1322963	NM_000152.5(GAA):c.309C>A (p.Cys103Ter)	GAA	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 18 · 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
GAA	Definitive	Autosomal recessive	glycogen storage disease II	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CCDC40	Orphanet:244	Primary ciliary dyskinesia
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly

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
GAA	HGNC:4065	ENSG00000171298	P10253	Lysosomal alpha-glucosidase	gencc,clinvar
CCDC40	HGNC:26090	ENSG00000141519	Q4G0X9	Coiled-coil domain-containing protein 40	clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GAA	Lysosomal alpha-glucosidase	Essential for the degradation of glycogen in lysosomes.
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.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

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
Kinase	1	9.2×	0.313
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GAA	Enzyme (other)	yes	3.2.1.20	Glyco_hydro_31_TIM, P_trefoil_dom, Gal_mutarotase_sf_dom
CCDC40	Other/Unknown	no		CCDC40
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

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
granulocyte	1
left testis	1
right testis	1
bronchial epithelial cell	1
right uterine tube	1
sural nerve	1
adrenal tissue	1
calcaneal tendon	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GAA	261	ubiquitous	marker	granulocyte, left testis, right testis
CCDC40	184	ubiquitous	marker	right uterine tube, bronchial epithelial cell, sural nerve
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3CA	5,157
GAA	2,116
CCDC40	1,527

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135
GAA	P10253	19
CCDC40	Q4G0X9	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 72. 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
Glycogen storage diseases	1	2855.0×	0.008	GAA
Glycogen storage disease type II (GAA)	1	2855.0×	0.008	GAA
MET activates PI3K/AKT signaling	1	951.7×	0.008	PIK3CA
Glycogen metabolism	1	951.7×	0.008	GAA
Activated NTRK3 signals through PI3K	1	951.7×	0.008	PIK3CA
Activated NTRK2 signals through PI3K	1	815.7×	0.008	PIK3CA
Signaling by LTK in cancer	1	815.7×	0.008	PIK3CA
PI3K/AKT activation	1	634.4×	0.008	PIK3CA
IRS-mediated signalling	1	519.1×	0.008	PIK3CA
PI3K events in ERBB4 signaling	1	519.1×	0.008	PIK3CA
Co-stimulation by ICOS	1	519.1×	0.008	PIK3CA
Signaling by FGFR4 in disease	1	475.8×	0.008	PIK3CA
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	475.8×	0.008	PIK3CA
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	439.2×	0.008	PIK3CA
Signaling by PDGFRA extracellular domain mutants	1	439.2×	0.008	PIK3CA
Signaling by LTK	1	439.2×	0.008	PIK3CA
Diseases of carbohydrate metabolism	1	407.9×	0.008	GAA
Glycogen breakdown (glycogenolysis)	1	380.7×	0.008	GAA
Signaling by FLT3 ITD and TKD mutants	1	380.7×	0.008	PIK3CA
Constitutive Signaling by EGFRvIII	1	356.9×	0.008	PIK3CA
PI3K events in ERBB2 signaling	1	335.9×	0.008	PIK3CA
Signaling by ERBB2 ECD mutants	1	335.9×	0.008	PIK3CA
GAB1 signalosome	1	317.2×	0.008	PIK3CA
Signaling by cytosolic FGFR1 fusion mutants	1	317.2×	0.008	PIK3CA
PI-3K cascade:FGFR3	1	317.2×	0.008	PIK3CA
Tie2 Signaling	1	300.5×	0.008	PIK3CA
Role of LAT2/NTAL/LAB on calcium mobilization	1	300.5×	0.008	PIK3CA
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	285.5×	0.008	PIK3CA
Signaling by ALK	1	285.5×	0.008	PIK3CA
PI-3K cascade:FGFR4	1	285.5×	0.008	PIK3CA

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
cardiac muscle contraction	2	267.5×	0.001	GAA, PIK3CA
glucose metabolic process	2	170.2×	0.002	GAA, PIK3CA
maltose metabolic process	1	5617.3×	0.002	GAA
sucrose metabolic process	1	5617.3×	0.002	GAA
response to muscle inactivity	1	5617.3×	0.002	PIK3CA
obsolete vacuolar sequestering	1	5617.3×	0.002	GAA
response to butyrate	1	5617.3×	0.002	PIK3CA
response to L-leucine	1	1872.4×	0.005	PIK3CA
cellular response to hydrostatic pressure	1	1872.4×	0.005	PIK3CA
diaphragm contraction	1	1404.3×	0.006	GAA
determination of pancreatic left/right asymmetry	1	1123.5×	0.006	CCDC40
negative regulation of actin filament depolymerization	1	936.2×	0.006	PIK3CA
regulation of cellular respiration	1	936.2×	0.006	PIK3CA
determination of digestive tract left/right asymmetry	1	936.2×	0.006	CCDC40
determination of liver left/right asymmetry	1	936.2×	0.006	CCDC40
regulation of actin filament organization	1	802.5×	0.006	PIK3CA
autosome genomic imprinting	1	802.5×	0.006	PIK3CA
negative regulation of fibroblast apoptotic process	1	802.5×	0.006	PIK3CA
regulation of cilium beat frequency	1	702.2×	0.006	CCDC40
tissue development	1	624.1×	0.006	GAA
cardiac muscle cell contraction	1	561.7×	0.006	PIK3CA
positive regulation of protein localization to membrane	1	561.7×	0.006	PIK3CA
TORC2 signaling	1	510.7×	0.007	PIK3CA
glycophagy	1	468.1×	0.007	GAA
phosphatidylinositol-3-phosphate biosynthetic process	1	432.1×	0.007	PIK3CA
anoikis	1	432.1×	0.007	PIK3CA
relaxation of cardiac muscle	1	432.1×	0.007	PIK3CA
epithelial cilium movement involved in determination of left/right asymmetry	1	432.1×	0.007	CCDC40
glycogen catabolic process	1	401.2×	0.007	GAA
response to dexamethasone	1	401.2×	0.007	PIK3CA

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
GAA	DIENESTROL
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GAA	112	4
PIK3CA	67	4
CCDC40	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIENESTROL	4	GAA
MIGLUSTAT	4	GAA
DICLOFENAC SODIUM	4	GAA
DIBUCAINE	4	GAA
AMLEXANOX	4	GAA
MIGALASTAT	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
DOPAMINE HYDROCHLORIDE	4	GAA
PRAZOSIN HYDROCHLORIDE	4	GAA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
GAA	280	Binding:267, Functional:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GAA	3.2.1.20	alpha-glucosidase
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GAA	280
PIK3CA	2,034

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

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)
DIENESTROL	4	GAA
DICLOFENAC SODIUM	4	GAA
DIBUCAINE	4	GAA
AMLEXANOX	4	GAA
MIGALASTAT	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
DOPAMINE HYDROCHLORIDE	4	GAA
PRAZOSIN HYDROCHLORIDE	4	GAA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	GAA, PIK3CA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CCDC40

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CCDC40	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 124.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	71
PHASE4	16
PHASE2	11
PHASE1/PHASE2	11
PHASE3	6
PHASE1	5
PHASE2/PHASE3	2
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05164055	PHASE4	ACTIVE_NOT_RECRUITING	Avalglucosidase Alfa French Post-trial Access for Participants With Pompe Disease (PTA Avalglucosidase)
NCT06575829	PHASE4	NOT_YET_RECRUITING	Treatment Frequency Reduction in Pompe Disease
NCT06666413	PHASE4	RECRUITING	China Post-approval Commitment (PAC) Study of Avalglucosidase Alfa in Participants With IOPD
NCT00455195	PHASE4	COMPLETED	Late-Onset Treatment Study Extension Protocol
NCT00483379	PHASE4	COMPLETED	High Dose or High Dose Frequency Study of Alglucosidase Alfa
NCT00486889	PHASE4	COMPLETED	Growth and Development Study of Alglucosidase Alfa
NCT00701129	PHASE4	COMPLETED	An Exploratory Study of the Safety and Efficacy of Prophylactic Immunomodulatory Treatment in Myozyme-naive Cross-Reacting Immunologic Material (CRIM[-]) Patients With Infantile-Onset Pompe Disease
NCT00701701	PHASE4	TERMINATED	Immune Tolerance Induction Study
NCT01288027	PHASE4	COMPLETED	Exploratory Muscle Biopsy Assessment Study in Patients With Late-Onset Pompe Disease Treated With Alglucosidase Alfa
NCT01410890	PHASE4	COMPLETED	Pharmacokinetics of Alglucosidase Alfa in Patients With Pompe Disease
NCT01526785	PHASE4	TERMINATED	A Study to Evaluate the Efficacy and Safety of Alglucosidase Alfa Produced at the 4000 L Scale for Pompe Disease
NCT01597596	PHASE4	TERMINATED	A Noninferiority Study of Alglucosidase Alfa Manufactured at the 160 L and 4000 L Scales in Treatment Naïve Patients With Infantile-Onset Pompe Disease
NCT02405598	PHASE4	COMPLETED	Evaluation of Salbutamol as an Adjuvant Therapy for Pompe Disease
NCT02405624	PHASE4	UNKNOWN	CPAP for Infantile Pompe Disease
NCT02525172	PHASE4	UNKNOWN	Immune Modulation Therapy for Pompe Disease
NCT03687333	PHASE4	COMPLETED	Evaluate Efficacy and Safety in Chinese Patients With Infantile-Onset Pompe Disease With One Year Alglucosidase Alfa Treatment
NCT03911505	PHASE3	ACTIVE_NOT_RECRUITING	ZIP Study-OL Study of Safety, PK, Efficacy, PD, Immunogenicity of ATB200/AT2221 in Pediatrics Aged 0 to < 18 y.o. w/LOPD
NCT04910776	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Study for Treatment-naïve IOPD Babies to Evaluate Efficacy and Safety of ERT With Avalglucosidase Alfa
NCT00059280	PHASE2/PHASE3	COMPLETED	A Study of the Safety and Efficacy of rhGAA in Patients With Infantile-onset Pompe Disease
NCT00125879	PHASE2/PHASE3	COMPLETED	Extension Study of Patients With Infantile-Onset Pompe Disease Who Were Previously Enrolled in Protocol AGLU01602
NCT00158600	PHASE3	COMPLETED	A Placebo-Controlled Study of Safety and Effectiveness of Myozyme (Alglucosidase Alfa) in Patients With Late-Onset Pompe Disease
NCT00268944	PHASE3	COMPLETED	Safety and Effectiveness Study of rhGAA in Patients With Advanced Late-Onset Pompe Disease Receiving Respiratory Support
NCT03729362	PHASE3	COMPLETED	A Study Comparing ATB200/AT2221 With Alglucosidase Alfa/Placebo in Adult Subjects With Late-onset Pompe Disease
NCT04138277	PHASE3	COMPLETED	A Study to Assess the Long-term Safety and Efficacy of ATB200/AT2221 in Adult Subjects With Late-Onset Pompe Disease (LOPD)
NCT04093349	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Gene Transfer Study for Late-Onset Pompe Disease (RESOLUTE)
NCT04174105	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Gene Transfer Study in Patients With Late Onset Pompe Disease
NCT06391736	PHASE1/PHASE2	RECRUITING	Evaluation of the Safety and Efficacy of Late-onset Pompe Disease Gene Therapy Drug
NCT07123155	PHASE2	RECRUITING	Study of S-606001 as an Add-on to Enzyme Replacement Therapy (ERT) in Participants With Late-onset Pompe Disease (LOPD)
NCT07282847	PHASE1/PHASE2	RECRUITING	A Study to Evaluate Safety, Tolerability, and Efficacy of AB-1009 Gene Therapy (GAA Gene) in Adult Participants With Late Onset Pompe Disease (PROGRESS-GT LOPD)
NCT00025896	PHASE2	COMPLETED	Safety and Efficacy of Recombinant Human Acid Alpha-Glucosidase in the Treatment of Classical Infantile Pompe Disease
NCT00051935	PHASE2	COMPLETED	A Study of the Safety and Pharmacokinetics of rhGAA in Siblings With Glycogen Storage Disease Type II
NCT00053573	PHASE1/PHASE2	COMPLETED	rhGAA in Patients With Infantile-onset Glycogen Storage Disease-II (Pompe Disease)
NCT00250939	PHASE2	COMPLETED	A Study of rhGAA in Patients With Late-Onset Pompe Disease
NCT00688597	PHASE2	TERMINATED	Study to Evaluate the Safety of AT2220 (Duvoglustat) in Pompe Disease
NCT00763932	PHASE2	COMPLETED	Extension Study of Long-term Safety and Efficacy of Myozyme in Patients With Pompe Disease Who Were Previously Enrolled in Genzyme Sponsored Enzyme Replacement Therapy (ERT) Studies
NCT00976352	PHASE1/PHASE2	COMPLETED	Safety Study of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase to Treat Pompe Disease
NCT01230801	PHASE1/PHASE2	COMPLETED	Safety/Tolerability/Pharmacokinetic (PK)/Pharmacodynamics (PD) Study of BMN701 in Patients With Late-Onset Pompe Disease
NCT01380743	PHASE2	COMPLETED	Drug-drug Interaction Study
NCT01435772	PHASE2	TERMINATED	Extension Study for Patients Who Have Participated in a BMN 701 Study
NCT01656590	PHASE2	WITHDRAWN	High Protein and Exercise Therapy Plus Nocturnal Enteral Feeding in Juvenile-onset Pompe Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALGLUCOSIDASE ALFA	4	25
CIPAGLUCOSIDASE ALFA	4	6
AVALGLUCOSIDASE ALFA	4	5
MIGLUSTAT	4	4
RITUXIMAB	4	4
METHOTREXATE	4	2
PYRIDOSTIGMINE	4	2
ALBUTEROL	4	1
BORTEZOMIB	4	1
REVEGLUCOSIDASE ALFA	3	2
CLENBUTEROL	2	2
DUVOGLUSTAT	2	2
CLERVONAFUSP ALFA	2	1
ZOCAGLUSAGENE NUZAPARVOVEC	2	1
VANGLUSAGENE ENSIPARVOVEC	1	1
CHEMBL426	0	2