Fabry disease

disease

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Also known as Alpha-galactosidase A deficiencyAnderson-Fabry diseaseangiokeratoma corporis diffusumangiokeratoma, diffusediffuse angiokeratomaFabry's diseaseFD

Summary

Fabry disease (MONDO:0010526) is a disease caused by GLA (GenCC Definitive), with 7 cohort genes and 226 clinical trials. Top therapeutic interventions include migalastat, agalsidase alfa, and agalsidase beta.

At a glance

Prevalence: 1-9 / 1 000 000 (United Kingdom) [Orphanet-validated]
Causal gene: GLA (GenCC Definitive)
Cohort genes: 7
ClinVar variants: 1,879
Phenotypes (HPO): 76
Clinical trials: 226

Clinical features

Epidemiology

Prevalence records

11 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	6.66	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.15	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000	0.118	China	Validated
Prevalence at birth	1-9 / 1 000 000	6.96	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.21	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.12	Portugal	Validated
Prevalence at birth	1-9 / 1 000 000	0.52	Czech Republic	Validated
Prevalence at birth	<1 / 1 000 000	0.015	Turkey	Validated
Prevalence at birth	1-9 / 1 000 000	0.25	Japan	Validated
Prevalence at birth	1-9 / 100 000	1.11	Sweden	Validated
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000083	Renal insufficiency	Very frequent (80-99%)
HP:0000100	Nephrotic syndrome	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000524	Conjunctival telangiectasia	Very frequent (80-99%)
HP:0000790	Hematuria	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0000966	Hypohidrosis	Very frequent (80-99%)
HP:0001014	Angiokeratoma	Very frequent (80-99%)
HP:0001131	Corneal dystrophy	Very frequent (80-99%)
HP:0001369	Arthritis	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Very frequent (80-99%)
HP:0001635	Congestive heart failure	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0002024	Malabsorption	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0002326	Transient ischemic attack	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003326	Myalgia	Very frequent (80-99%)
HP:0004343	Abnormal glycosphingolipid metabolism	Very frequent (80-99%)
HP:0007957	Corneal opacity	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0033595	Elevated circulating globotriaosylceramide concentration	Very frequent (80-99%)
HP:0034864	Decreased alpha-galactosidase A activity	Very frequent (80-99%)
HP:0100579	Mucosal telangiectasiae	Very frequent (80-99%)
HP:0100585	Telangiectasia of the skin	Very frequent (80-99%)
HP:0000091	Abnormal renal tubule morphology	Frequent (30-79%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000112	Nephropathy	Frequent (30-79%)
HP:0000179	Thick lower lip vermilion	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000360	Tinnitus	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0001646	Abnormal aortic valve morphology	Frequent (30-79%)
HP:0001653	Mitral regurgitation	Frequent (30-79%)
HP:0001678	Atrioventricular block	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0002046	Heat intolerance	Frequent (30-79%)
HP:0002097	Emphysema	Frequent (30-79%)
HP:0003077	Hyperlipidemia	Frequent (30-79%)
HP:0003119	Abnormal circulating lipid concentration	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0011710	Bundle branch block	Frequent (30-79%)
HP:0012532	Chronic pain	Frequent (30-79%)
HP:0031006	Acroparesthesia	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Fabry disease
Mondo ID	MONDO:0010526
MeSH	D000795
OMIM	301500
Orphanet	324
DOID	DOID:14499
ICD-11	66996647
NCIT	C84701
SNOMED CT	16652001
UMLS	C0002986
MedGen	8083
GARD	0006400
MedDRA	10016016
NORD	1115
Is cancer (heuristic)	no

Also known as: Alpha-galactosidase A deficiency · Anderson-Fabry disease · angiokeratoma corporis diffusum · angiokeratoma, diffuse · diffuse angiokeratoma · Fabry disease · Fabry’s disease · FD · Fd

Data availability: 1,879 ClinVar variants · 5 GenCC gene-disease records · 67 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › Fabry disease

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:

153 pathogenic, 125 uncertain significance, 108 likely benign, 88 pathogenic/likely pathogenic, 64 conflicting classifications of pathogenicity, 48 likely pathogenic, 8 benign, 4 benign/likely benign, 1 benign/likely benign; other, 1 vus-mid

ClinVar	Variant (HGVS)	Gene	Classification	Review
10714	NM_000169.3(GLA):c.[370-183_547+41del;370-192A>C]		Pathogenic	no assertion criteria provided
10723	NM_000169.2(GLA):c.[196G>C;334C>T]		Pathogenic	no assertion criteria provided
2422510	NC_000023.10:g.(?100499986)(100662891_?)del	DRP2	Pathogenic	criteria provided, single submitter
1027590	NM_000169.3(GLA):c.242G>C (p.Trp81Ser)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
1050824	NM_000169.3(GLA):c.800T>G (p.Met267Arg)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1050825	NM_000169.3(GLA):c.969del (p.Leu324fs)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1059587	NM_000169.3(GLA):c.547+3A>G	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
1064716	NM_000169.3(GLA):c.453C>G (p.Tyr151Ter)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
1064717	NM_000169.3(GLA):c.835C>T (p.Gln279Ter)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
1064718	NM_000169.3(GLA):c.280T>A (p.Cys94Ser)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064719	NM_000169.3(GLA):c.924A>C (p.Lys308Asn)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065155	NM_000169.3(GLA):c.3G>A (p.Met1Ile)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069600	NM_000169.3(GLA):c.379A>T (p.Lys127Ter)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
1070568	NM_000169.3(GLA):c.437del (p.Pro146fs)	GLA	Pathogenic	criteria provided, single submitter
1071124	NM_000169.3(GLA):c.1235C>T (p.Thr412Ile)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10713	NM_000169.3(GLA):c.1066C>T (p.Arg356Trp)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10715	NM_000169.3(GLA):c.902G>A (p.Arg301Gln)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
10716	NM_000169.3(GLA):c.131G>A (p.Trp44Ter)	GLA	Pathogenic	criteria provided, single submitter
10717	NM_000169.3(GLA):c.886A>G (p.Met296Val)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10718	NM_000169.3(GLA):c.370-1G>A	GLA	Pathogenic	no assertion criteria provided
10719	NM_000169.3(GLA):c.118C>T (p.Pro40Ser)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
10720	NM_000169.3(GLA):c.999+1G>T	GLA	Pathogenic	criteria provided, single submitter
10721	NM_000169.3(GLA):c.835C>G (p.Gln279Glu)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10722	NM_000169.3(GLA):c.982G>A (p.Gly328Arg)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
10724	NM_000169.3(GLA):c.101A>G (p.Asn34Ser)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
10725	NM_000169.3(GLA):c.166T>G (p.Cys56Gly)	GLA	Pathogenic	criteria provided, single submitter
10727	NM_000169.3(GLA):c.466G>A (p.Ala156Thr)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10728	NM_000169.3(GLA):c.484T>C (p.Trp162Arg)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10729	NM_000169.3(GLA):c.606T>G (p.Cys202Trp)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
10730	NM_000169.3(GLA):c.644A>G (p.Asn215Ser)	GLA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · 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
GLA	Definitive	X-linked	Fabry disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLA	Orphanet:324	Fabry disease
BTK	Orphanet:47	X-linked agammaglobulinemia
BTK	Orphanet:632	Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
DPYSL2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
GALC	Orphanet:206436	Infantile Krabbe disease
GALC	Orphanet:206443	Late-infantile/juvenile Krabbe disease
GALC	Orphanet:206448	Adult Krabbe disease

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLA	HGNC:4296	ENSG00000102393	P06280	Alpha-galactosidase A	gencc,clinvar
BTK	HGNC:1133	ENSG00000010671	Q06187	Tyrosine-protein kinase BTK	clinvar
MYLK2	HGNC:16243	ENSG00000101306	Q9H1R3	Myosin light chain kinase 2, skeletal/cardiac muscle	clinvar
DPYSL2	HGNC:3014	ENSG00000092964	Q16555	Dihydropyrimidinase-related protein 2	clinvar
DRP2	HGNC:3032	ENSG00000102385	Q13474	Dystrophin-related protein 2	clinvar
GALC	HGNC:4115	ENSG00000054983	P54803	Galactocerebrosidase	clinvar
RPL36A-HNRNPH2	HGNC:48349	ENSG00000257529		RPL36A-HNRNPH2 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLA	Alpha-galactosidase A	Catalyzes the hydrolysis of glycosphingolipids and participates in their degradation in the lysosome.
BTK	Tyrosine-protein kinase BTK	Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling.
MYLK2	Myosin light chain kinase 2, skeletal/cardiac muscle	Implicated in the level of global muscle contraction and cardiac function.
DPYSL2	Dihydropyrimidinase-related protein 2	Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration.
DRP2	Dystrophin-related protein 2	Required for normal myelination and for normal organization of the cytoplasm and the formation of Cajal bands in myelinating Schwann cells.
GALC	Galactocerebrosidase	Hydrolyzes the galactose ester bonds of glycolipids such as galactosylceramide and galactosylsphingosine.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.57

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	2	7.9×	0.097
Enzyme (other)	2	3.4×	0.220
Transcription factor	1	1.2×	0.793
Other/Unknown	2	0.5×	0.968

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLA	Enzyme (other)	yes	3.2.1.22	Glyco_hydro_27/36_CS, Glyco_hydro_27, Glyco_hydro_b
BTK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
MYLK2	Kinase	yes	2.7.11.18	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
DPYSL2	Other/Unknown	no		Amidohydro-rel, Metal-dep_hydrolase_composite, Hydantoinase/dihydroPyrase
DRP2	Transcription factor	no		Znf_ZZ, WW_dom, Spectrin_repeat
GALC	Enzyme (other)	yes	3.2.1.46	Glyco_hydro_59, Aldolase_TIM, GH_hydrolase_sf
RPL36A-HNRNPH2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	2
mononuclear cell	2
pancreatic ductal cell	1
leukocyte	1
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
inferior vagus X ganglion	1
substantia nigra pars compacta	1
subthalamic nucleus	1
dorsal root ganglion	1
tibial nerve	1
trigeminal ganglion	1
adrenal tissue	1
bronchial epithelial cell	1
jejunal mucosa	1
islet of Langerhans	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLA	263	ubiquitous	marker	pancreatic ductal cell, monocyte, mononuclear cell
BTK	206	broad	marker	monocyte, mononuclear cell, leukocyte
MYLK2	148	tissue_specific	yes	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, gastrocnemius
DPYSL2	301	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, substantia nigra pars compacta
DRP2	151	broad	marker	trigeminal ganglion, tibial nerve, dorsal root ganglion
GALC	295	ubiquitous	marker	adrenal tissue, bronchial epithelial cell, jejunal mucosa
RPL36A-HNRNPH2	134	ubiquitous	marker	left ovary, right ovary, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BTK	4,467
DPYSL2	2,980
MYLK2	2,040
GLA	1,826
GALC	1,154
DRP2	637
RPL36A-HNRNPH2	0

Intra-cohort edges

A	B	Sources
BTK	DRP2	string_interaction
GALC	GLA	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BTK	Q06187	156
GLA	P06280	31
DPYSL2	Q16555	15
MYLK2	Q9H1R3	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GALC	P54803	94.56
DRP2	Q13474	74.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 55. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid catabolism	2	117.1×	0.006	GLA, GALC
G-protein beta:gamma signalling	1	380.7×	0.043	BTK
Diseases of Immune System	1	175.7×	0.043	BTK
Diseases associated with the TLR signaling cascade	1	175.7×	0.043	BTK
CRMPs in Sema3A signaling	1	126.9×	0.043	DPYSL2
G beta:gamma signalling through BTK	1	126.9×	0.043	BTK
MyD88 deficiency (TLR2/4)	1	120.2×	0.043	BTK
IRAK4 deficiency (TLR2/4)	1	114.2×	0.043	BTK
DAP12 interactions	1	95.2×	0.043	BTK
DAP12 signaling	1	73.7×	0.043	BTK
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	73.7×	0.043	DRP2
FCERI mediated Ca+2 mobilization	1	71.4×	0.043	BTK
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	71.4×	0.043	BTK
Parasite infection	1	69.2×	0.043	BTK
Leishmania phagocytosis	1	69.2×	0.043	BTK
Signaling by the B Cell Receptor (BCR)	1	69.2×	0.043	BTK
Antigen processing-Cross presentation	1	63.4×	0.043	BTK
RHO GTPases Activate WASPs and WAVEs	1	63.4×	0.043	BTK
Formation of the dystrophin-glycoprotein complex (DGC)	1	61.7×	0.043	DRP2
Glycosphingolipid metabolism	1	60.1×	0.043	GLA
Innate Immune System	2	10.2×	0.043	GLA, BTK
Fcgamma receptor (FCGR) dependent phagocytosis	1	55.7×	0.044	BTK
Fc epsilon receptor (FCERI) signaling	1	54.4×	0.044	BTK
Recycling pathway of L1	1	44.8×	0.051	DPYSL2
FCGR3A-mediated phagocytosis	1	37.4×	0.052	BTK
Regulation of actin dynamics for phagocytic cup formation	1	36.8×	0.052	BTK
Toll Like Receptor TLR6:TLR2 Cascade	1	35.1×	0.052	BTK
Toll Like Receptor 2 (TLR2) Cascade	1	34.6×	0.052	BTK
Toll Like Receptor TLR1:TLR2 Cascade	1	33.6×	0.052	BTK
Sphingolipid metabolism	1	33.6×	0.052	GLA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycosphingolipid catabolic process	2	510.7×	4e-04	GLA, GALC
regulation of B cell cytokine production	1	2808.7×	0.005	BTK
monocyte proliferation	1	2808.7×	0.005	BTK
positive regulation of interleukin-17A production	1	2808.7×	0.005	BTK
positive regulation of type I hypersensitivity	1	1404.3×	0.005	BTK
B cell affinity maturation	1	1404.3×	0.005	BTK
regulation of B cell apoptotic process	1	1404.3×	0.005	BTK
galactosylceramide catabolic process	1	1404.3×	0.005	GALC
regulation of muscle filament sliding	1	1404.3×	0.005	MYLK2
negative regulation of nitric-oxide synthase activity	1	1404.3×	0.005	GLA
positive regulation of type III hypersensitivity	1	936.2×	0.005	BTK
proteoglycan catabolic process	1	936.2×	0.005	BTK
glycosylceramide catabolic process	1	936.2×	0.005	GLA
positive regulation of synoviocyte proliferation	1	936.2×	0.005	BTK
eosinophil homeostasis	1	936.2×	0.005	BTK
cellular response to molecule of fungal origin	1	702.2×	0.006	BTK
histamine secretion by mast cell	1	561.7×	0.007	BTK
glycoside catabolic process	1	468.1×	0.008	GLA
skeletal muscle satellite cell differentiation	1	351.1×	0.010	MYLK2
positive regulation of cGAS/STING signaling pathway	1	351.1×	0.010	BTK
neutrophil homeostasis	1	255.3×	0.012	BTK
synaptic signaling	1	255.3×	0.012	DRP2
cardiac muscle tissue morphogenesis	1	234.1×	0.013	MYLK2
cellular response to interleukin-7	1	216.1×	0.013	BTK
positive regulation of B cell differentiation	1	187.2×	0.014	BTK
negative regulation of nitric oxide biosynthetic process	1	165.2×	0.016	GLA
MyD88-dependent toll-like receptor signaling pathway	1	156.0×	0.016	BTK
negative regulation of B cell proliferation	1	156.0×	0.016	BTK
peptidyl-threonine phosphorylation	1	147.8×	0.016	MYLK2
striated muscle contraction	1	140.4×	0.016	MYLK2

Therapeutics

Drugs indicated for this disease

3 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Agalsidase Alfa	Approved (phase 4)
Agalsidase Beta	Approved (phase 4)
Pegunigalsidase Alfa	Approved (phase 4)
Lucerastat	Phase 3 (in late-stage trials)
Migalastat	Phase 3 (in late-stage trials)
Tilactase	Phase 3 (in late-stage trials)
Venglustat	Phase 3 (in late-stage trials)

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

Drug target analysis

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

Druggability breadth: 5 of 7 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
GLA	CLOTRIMAZOLE
BTK	PONATINIB
MYLK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BTK	84	4
GLA	62	4
MYLK2	19	4
DPYSL2	0	0
DRP2	0	0
GALC	0	0
RPL36A-HNRNPH2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	GLA
METHYSERGIDE	4	GLA
MIGALASTAT	4	GLA
PINACIDIL ANHYDROUS	4	GLA
DOXAZOSIN MESYLATE	4	GLA
AMPICILLIN SODIUM	4	GLA
PHENOXYBENZAMINE HYDROCHLORIDE	4	GLA
METHYSERGIDE MALEATE	4	GLA
ACRISORCIN	4	GLA
NOMIFENSINE MALEATE	4	GLA
INAMRINONE	4	GLA
AMILORIDE HYDROCHLORIDE	4	GLA
PHENOL	4	GLA
FLUPHENAZINE HYDROCHLORIDE	4	GLA
PRAZOSIN HYDROCHLORIDE	4	GLA
PSEUDOEPHEDRINE	4	GLA
PHENYTOIN SODIUM	4	GLA
RIBAVIRIN	4	GLA
SOTALOL HYDROCHLORIDE	4	GLA
DIGOXIN	4	GLA
PRAZOSIN	4	GLA
DOMPERIDONE	4	GLA
CIMETIDINE	4	GLA
MASOPROCOL	4	GLA
METHOTREXATE	4	GLA
AMSACRINE	4	GLA
LANSOPRAZOLE	4	GLA
PINDOLOL	4	GLA
NIMESULIDE	4	GLA
TRIAMTERENE	4	GLA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
BTK	1,836	Binding:1810, Functional:23, ADMET:3
MYLK2	196	Binding:196
GLA	114	Binding:104, Functional:10
DPYSL2	3	Binding:3
GALC	3	Binding:2, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GLA	3.2.1.22	alpha-galactosidase
BTK	2.7.10.2	non-specific protein-tyrosine kinase
MYLK2	2.7.11.18	myosin-light-chain kinase
GALC	3.2.1.46	galactosylceramidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GLA	114
BTK	1,836
MYLK2	196

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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)
CLOTRIMAZOLE	4	GLA
METHYSERGIDE	4	GLA
PINACIDIL ANHYDROUS	4	GLA
DOXAZOSIN MESYLATE	4	GLA
AMPICILLIN SODIUM	4	GLA
PHENOXYBENZAMINE HYDROCHLORIDE	4	GLA
METHYSERGIDE MALEATE	4	GLA
ACRISORCIN	4	GLA
NOMIFENSINE MALEATE	4	GLA
INAMRINONE	4	GLA
AMILORIDE HYDROCHLORIDE	4	GLA
PHENOL	4	GLA
FLUPHENAZINE HYDROCHLORIDE	4	GLA
PRAZOSIN HYDROCHLORIDE	4	GLA
PSEUDOEPHEDRINE	4	GLA
PHENYTOIN SODIUM	4	GLA
RIBAVIRIN	4	GLA
SOTALOL HYDROCHLORIDE	4	GLA
DIGOXIN	4	GLA
PRAZOSIN	4	GLA
DOMPERIDONE	4	GLA
CIMETIDINE	4	GLA
MASOPROCOL	4	GLA
METHOTREXATE	4	GLA
AMSACRINE	4	GLA
LANSOPRAZOLE	4	GLA
PINDOLOL	4	GLA
NIMESULIDE	4	GLA
TRIAMTERENE	4	GLA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	GLA, BTK, MYLK2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	GALC
E	Difficult family or no structure, no drug	3	DPYSL2, DRP2, RPL36A-HNRNPH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DRP2	0	BTK
DPYSL2	3	—
GALC	3	—
RPL36A-HNRNPH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 226.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	139
PHASE3	27
PHASE2	21
PHASE4	13
PHASE1	12
PHASE1/PHASE2	11
PHASE2/PHASE3	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05067868	PHASE4	RECRUITING	A Study of Replagal in Children and Adults With Fabry Disease in India
NCT00074984	PHASE4	COMPLETED	A Study of the Safety and Efficacy of Fabrazyme (Agalsidase Beta) as Compared to Placebo in Patients With Advanced Fabry Disease
NCT00081497	PHASE4	COMPLETED	A Study of the Safety and Efficacy of Fabrazyme in Patients With Fabry Disease
NCT00097890	PHASE4	COMPLETED	Replagal Enzyme Replacement Therapy for Adults With Fabry Disease
NCT00140621	PHASE4	COMPLETED	A Safety and Efficacy Study of Fabrazyme® Replacement Therapy in Patients With Cardiac Fabry Disease
NCT00230607	PHASE4	TERMINATED	Study of the Effects of Fabrazyme Treatment on Lactation and Infants
NCT00312767	PHASE4	WITHDRAWN	A Study in Patients With Fabry Disease Who Are on Chronic Hemodialysis Therapy for Treatment of End-stage Renal Insufficiency.
NCT00487630	PHASE4	UNKNOWN	Evaluation of Efficacy and Safety of Agalsidase Beta in Heterozygous Females for Fabry Disease
NCT01650779	PHASE4	COMPLETED	A Study Evaluating Glycosphingolipid Clearance in Patients Treated With Agalsidase Alfa Who Switch to Agalsidase Beta
NCT01997489	PHASE4	COMPLETED	Ophthalmic Findings During 10-year Enzyme Substitution of Danish Fabry Patients.
NCT04143958	PHASE4	WITHDRAWN	To Assess the Glycosphingolipid Clearance and Clinical Effects of Switching to Agalsidase Beta (Fabrazyme) Versus Continuing on Agalsidase Alfa (Replagal) in Male Patients With Classic Fabry Disease
NCT05054387	PHASE4	COMPLETED	China Post-marketing Surveillance (PMS) Study of Fabrazyme®
NCT06019728	PHASE4	COMPLETED	A Prospective Study to Investigate Safety and Tolerability of Shorter Infusion of Fabrazyme
NCT03737214	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Long-term Safety and Tolerability of Lucerastat in Adult Subjects With Fabry Disease
NCT04020055	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Migalastat in Fabry Subjects With Amenable GLA Variant and Renal Disease
NCT05206773	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Effect of Venglustat Tablets on Neuropathic and Abdominal Pain in Male and Female Participants ≥16 Years of Age With Fabry Disease
NCT05280548	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Effect of Venglustat Tablets on Left Ventricular Mass Index in Male and Female Adult Participants With Fabry Disease
NCT05710692	PHASE2/PHASE3	RECRUITING	Study to Evaluate the Safety, PK, PD, and Efficacy of PRX-102 in Japanese Patients With Fabry Disease
NCT06081062	PHASE3	RECRUITING	Evaluate the Safety and Efficacy of Fabagal® (Agalsidase Beta) in Patients With Fabry Disease
NCT06328608	PHASE2/PHASE3	RECRUITING	A Study to Learn About the Safety and Effects of the Study Drug PRX-102 in Children and Adolescents With Fabry Disease
NCT06904261	PHASE3	RECRUITING	A Study of Migalastat in Pediatric Subjects (2 to <12 Yrs) With Fabry Disease and Amenable GLA Variants
NCT00074971	PHASE3	COMPLETED	A Study of the Safety and Efficacy of Fabrazyme in Patients With Fabry Disease
NCT00701415	PHASE3	COMPLETED	A Study of Two Fabrazyme (Agalsidase Beta) Dosing Regimens in Treatment-naïve, Male Pediatric Patients Without Severe Symptoms
NCT00864851	PHASE3	COMPLETED	Safety and Efficacy Study of Several Replagal Dosing Regimens on Cardiac Function in Adults With Fabry Disease
NCT00925301	PHASE3	COMPLETED	Study of the Effects of Oral AT1001 (Migalastat Hydrochloride) in Patients With Fabry Disease
NCT01124643	PHASE3	COMPLETED	Extension Study of TKT028 Evaluating Safety and Clinical Outcomes of Replagal® in Adult Patients With Fabry Disease
NCT01218659	PHASE3	COMPLETED	Study to Compare the Efficacy and Safety of Oral AT1001 and Enzyme Replacement Therapy in Patients With Fabry Disease
NCT01298141	PHASE3	COMPLETED	A Multicenter Open-Label Treatment Protocol to Observe the Safety of Replagal (Agalsidase Alfa) Enzyme Replacement Therapy in Canadian Patients With Fabry Disease
NCT01458119	PHASE3	TERMINATED	Open-Label Phase 3 Long-Term Safety Study of Migalastat
NCT02194985	PHASE3	COMPLETED	Open-Label Extension Study of the Long-Term Effects of Migalastat HCL in Patients With Fabry Disease
NCT02795676	PHASE3	COMPLETED	Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function
NCT02921620	PHASE3	WITHDRAWN	Study to Evaluate the Safety and EffIcacy of PRX-102 on Gastrointestinal Symptoms in Naïve Fabry Disease
NCT03018730	PHASE3	COMPLETED	Safety and Efficacy of PRX-102 in Patients With Fabry Disease Currently Treated With REPLAGAL® (Agalsidase Alfa)
NCT03180840	PHASE3	COMPLETED	Safety, Efficacy, & PK of PRX-102 in Patients With Fabry Disease Administered Intravenously Every 4 Weeks
NCT03425539	PHASE3	COMPLETED	Efficacy and Safety of Lucerastat Oral Monotherapy in Adult Subjects With Fabry Disease
NCT03500094	PHASE3	COMPLETED	Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Migalastat in Pediatric Subjects (Aged 12 to <18 Years)
NCT03566017	PHASE3	COMPLETED	Open Label Extension Study of 1 mg/kg Pegunigalsidase Alfa Every 2 Weeks in Patients With Fabry Disease
NCT03614234	PHASE3	COMPLETED	Open Label Extension of 2 mg/kg Pegunigalsidase Alfa (PRX-102) Every 4 Weeks in Adult Fabry Disease Patients
NCT04049760	PHASE3	COMPLETED	Safety, Pharmacodynamics, and Efficacy of Migalastat in Pediatric Subjects (Aged >12 Years) With Fabry Disease
NCT04840667	PHASE3	TERMINATED	A Study of Replagal in Treatment-naïve Adults With Fabry Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MIGALASTAT	4	29
AGALSIDASE ALFA	4	19
AGALSIDASE BETA	4	12
PEGUNIGALSIDASE ALFA	4	9
ENALAPRIL	4	3
FEXOFENADINE	4	3
MONTELUKAST	4	3
ACETAMINOPHEN	4	1
CETIRIZINE	4	1
DIPHENHYDRAMINE	4	1
FLUORESCEIN	4	1
IOHEXOL	4	1
IOPAMIDOL	4	1
LORATADINE	4	1
PARICALCITOL	4	1
TROPICAMIDE	4	1
VENGLUSTAT	3	4
LUCERASTAT	3	3
APABETALONE	3	1
DUVOGLUSTAT	2	9
DUVALGAGENE OTIPARVOVEC	2	2
AL-01211	2	1
VOXERALGAGENE AUTOTEMCEL	1	1
CHEMBL5205127	0	1
CHEMBL1335195	0	1
CHEMBL177756	0	1
CHEMBL1457550	0	1

Cohort genes: GLA, BTK, MYLK2, DPYSL2, DRP2, GALC
Drugs: Migalastat, Agalsidase Alfa, Agalsidase Beta, Pegunigalsidase Alfa, Enalapril, Fexofenadine, Montelukast, Acetaminophen, Cetirizine, Diphenhydramine, Fluorescein, Iohexol, Iopamidol, Loratadine, Paricalcitol, Tropicamide, Venglustat, Lucerastat, Apabetalone