alpha thalassemia-X-linked intellectual disability syndrome

Summary

alpha thalassemia-X-linked intellectual disability syndrome (MONDO:0010519) is a disease caused by ATRX (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ATRX (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 2,245
• Phenotypes (HPO): 66

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000037	Male pseudohermaphroditism	Very frequent (80-99%)
HP:0000062	Ambiguous genitalia	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0002020	Gastroesophageal reflux	Very frequent (80-99%)
HP:0002381	Aphasia	Very frequent (80-99%)
HP:0010461	Abnormality of the male genitalia	Very frequent (80-99%)
HP:0011328	Abnormality of fontanelles	Very frequent (80-99%)
HP:0012368	Flat face	Very frequent (80-99%)
HP:0012736	Profound global developmental delay	Very frequent (80-99%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000179	Thick lower lip vermilion	Frequent (30-79%)
HP:0000232	Everted lower lip vermilion	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000457	Depressed nasal ridge	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0000717	Autism	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008736	Hypoplasia of penis	Frequent (30-79%)
HP:0010804	Tented upper lip vermilion	Frequent (30-79%)
HP:0010806	U-Shaped upper lip vermilion	Frequent (30-79%)
HP:0011800	Midface retrusion	Frequent (30-79%)
HP:0011902	Abnormal hemoglobin	Frequent (30-79%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001258	Spastic paraplegia	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001522	Death in infancy	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002017	Nausea and vomiting	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	alpha thalassemia-X-linked intellectual disability syndrome
Mondo ID	MONDO:0010519
MeSH	C538258
OMIM	301040
Orphanet	847
DOID	DOID:0110030
NCIT	C118631
SNOMED CT	715342005
UMLS	C1845055
MedGen	337145
GARD	0005864
NORD	753
Is cancer (heuristic)	no

Also known as: Alpha thalassemia intellectual disability syndrome, nondeletion type, X-linked · Alpha thalassemia mental retardation syndrome, nondeletion type, X-linked · Alpha Thalassemia X-linked Intellectual Disability Syndrome · Alpha thalassemia X-linked intellectual disability syndrome · Alpha thalassemia X-linked mental retardation syndrome · alpha thalassemia-X-linked intellectual disability syndrome · Alpha thalassemia/intellectual disability syndrome X-linked · Alpha thalassemia/mental retardation syndrome X-linked · Alpha-thalassemia X-linked intellectual disability syndrome · alpha-thalassemia/intellectual disability syndrome nondeletion type · ALPHA-thalassemia/intellectual disability syndrome, X-linked · Alpha-thalassemia/mental retardation syndrome, Nondeletion type · ALPHA-thalassemia/mental retardation syndrome, X-linked · alpha-thalassemia/mental retardation syndrome, X-linked dominant · ATR, nondeletion type · ATR-X syndrome · ATRX · ATRX syndrome · XLMR hypotonic face syndrome

Data availability: 2,245 ClinVar variants · 4 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › ATR-X-related syndrome › alpha thalassemia-X-linked intellectual disability syndrome

Related subtypes (1): intellectual disability-hypotonic facies syndrome, X-linked, 1

Genetics & variants

GWAS landscape

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

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

341 likely benign, 114 uncertain significance, 50 conflicting classifications of pathogenicity, 42 benign, 21 benign/likely benign, 17 pathogenic, 8 likely pathogenic, 6 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072204	NM_000489.6(ATRX):c.158del (p.Asn53fs)	ATRX	Pathogenic	criteria provided, single submitter
1072394	NC_000023.10:g.(?76759356)(77042755_?)del	ATRX	Pathogenic	criteria provided, single submitter
1072395	NC_000023.10:g.(?76937002)(76940508_?)del	ATRX	Pathogenic	criteria provided, single submitter
1073930	NM_000489.6(ATRX):c.1960C>T (p.Arg654Ter)	ATRX	Pathogenic	criteria provided, multiple submitters, no conflicts
11722	NM_000489.6(ATRX):c.4840T>C (p.Cys1614Arg)	ATRX	Pathogenic	no assertion criteria provided
11723	NM_000489.6(ATRX):c.4950G>T (p.Lys1650Asn)	ATRX	Pathogenic	no assertion criteria provided
11725	NM_000489.6(ATRX):c.6104A>T (p.Asp2035Val)	ATRX	Pathogenic	no assertion criteria provided
11726	NM_000489.6(ATRX):c.6250T>C (p.Tyr2084His)	ATRX	Pathogenic	no assertion criteria provided
11727	NM_000489.6(ATRX):c.6488A>G (p.Tyr2163Cys)	ATRX	Pathogenic	no assertion criteria provided
11728	NM_000489.6(ATRX):c.7156C>T (p.Arg2386Ter)	ATRX	Pathogenic	criteria provided, multiple submitters, no conflicts
11729	NM_000489.6(ATRX):c.7162G>T (p.Glu2388Ter)	ATRX	Pathogenic	no assertion criteria provided
11730	NM_000489.6(ATRX):c.5273-10T>A	ATRX	Pathogenic	no assertion criteria provided
11731	NM_000489.6(ATRX):c.6392G>A (p.Arg2131Gln)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11733	NM_000489.6(ATRX):c.751A>G (p.Lys251Glu)	ATRX	Pathogenic	no assertion criteria provided
11735	NM_000489.6(ATRX):c.736C>T (p.Arg246Cys)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11736	NM_000489.6(ATRX):c.5225G>A (p.Arg1742Lys)	ATRX	Pathogenic	no assertion criteria provided
11739	NM_000489.6(ATRX):c.4862C>T (p.Thr1621Met)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11742	NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11745	NM_000489.6(ATRX):c.659G>A (p.Cys220Tyr)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1180765	NM_000489.6(ATRX):c.6253C>T (p.Arg2085Cys)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334885	NM_000489.6(ATRX):c.6235C>T (p.Arg2079Ter)	ATRX	Pathogenic	criteria provided, single submitter
1441584	NM_000489.6(ATRX):c.2678dup (p.Thr894fs)	ATRX	Pathogenic	criteria provided, single submitter
1452479	NC_000023.10:g.(?76763809)(77041507_?)del	ATRX	Pathogenic	criteria provided, single submitter
1028792	NM_000489.6(ATRX):c.5449-7A>G	ATRX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067789	NM_000489.6(ATRX):c.485-1G>A	ATRX	Likely pathogenic	criteria provided, single submitter
11721	NM_000489.6(ATRX):c.4826A>G (p.His1609Arg)	ATRX	Likely pathogenic	criteria provided, single submitter
1172655	NM_000489.6(ATRX):c.5540A>G (p.Tyr1847Cys)	ATRX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
11734	NM_000489.6(ATRX):c.568C>G (p.Pro190Ala)	ATRX	Likely pathogenic	criteria provided, single submitter
1343274	NM_000489.6(ATRX):c.5281A>G (p.Met1761Val)	ATRX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1498207	NC_000023.10:g.(?76953051)(76954137_?)dup	ATRX	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 20 · 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
ATRX	Definitive	X-linked	alpha thalassemia-X-linked intellectual disability syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATRX	Orphanet:100075	Neuroendocrine tumor of stomach
ATRX	Orphanet:231401	Alpha-thalassemia-myelodysplastic syndrome
ATRX	Orphanet:847	X-linked alpha-thalassemia-intellectual disability syndrome
ATRX	Orphanet:96253	Cushing disease
GBA1	Orphanet:2072	Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
GBA1	Orphanet:411602	Hereditary late-onset Parkinson disease
GBA1	Orphanet:77259	Gaucher disease type 1
GBA1	Orphanet:77260	Gaucher disease type 2
GBA1	Orphanet:77261	Gaucher disease type 3
GBA1	Orphanet:85212	Fetal Gaucher disease
ALPL	Orphanet:247623	Perinatal lethal hypophosphatasia
ALPL	Orphanet:247638	Prenatal benign hypophosphatasia
ALPL	Orphanet:247651	Infantile hypophosphatasia
ALPL	Orphanet:247667	Childhood-onset hypophosphatasia
ALPL	Orphanet:247676	Adult hypophosphatasia
ALPL	Orphanet:247685	Odontohypophosphatasia
ATP7A	Orphanet:139557	X-linked distal spinal muscular atrophy type 3
ATP7A	Orphanet:198	Occipital horn syndrome
ATP7A	Orphanet:388	Hirschsprung disease
ATP7A	Orphanet:565	Menkes disease

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATRX	HGNC:886	ENSG00000085224	P46100	Transcriptional regulator ATRX	gencc,clinvar
GBA1	HGNC:4177	ENSG00000177628	P04062	Lysosomal acid glucosylceramidase	clinvar
ALPL	HGNC:438	ENSG00000162551	P05186	Alkaline phosphatase, tissue-nonspecific isozyme	clinvar
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATRX	Transcriptional regulator ATRX	Involved in transcriptional regulation and chromatin remodeling.
GBA1	Lysosomal acid glucosylceramidase	Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose.
ALPL	Alkaline phosphatase, tissue-nonspecific isozyme	Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis.
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.5

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
Phosphatase	1	21.0×	0.112
Transcription factor	2	4.1×	0.112
Enzyme (other)	1	3.0×	0.294

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATRX	Transcription factor	no		SNF2_N, Helicase_C-like, Znf_FYVE_PHD
GBA1	Enzyme (other)	yes	3.2.1.45	Glyco_hydro_30, GH_hydrolase_sf, GH30_C
ALPL	Phosphatase	yes	3.1.3.1	Alkaline_phosphatase, Alkaline_phosphatase_core_sf, Alkaline_phosphatase_AS
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
endothelial cell	1
islet of Langerhans	1
placenta	1
stromal cell of endometrium	1
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1
buccal mucosa cell	1
trabecular bone tissue	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATRX	294	ubiquitous	marker	endothelial cell, calcaneal tendon, colonic epithelium
GBA1	134	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, placenta
ALPL	200	broad	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland cortex
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATRX	5,796
ATP7A	3,901
GBA1	2,568
ALPL	2,146

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GBA1	P04062	58
ATP7A	Q04656	22
ATRX	P46100	12
ALPL	P05186	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alternative Lengthening of Telomeres (ALT)	1	2855.0×	0.003	ATRX
Defective Inhibition of DNA Recombination at Telomere	1	2855.0×	0.003	ATRX
Diseases of Telomere Maintenance	1	2855.0×	0.003	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations	1	1427.5×	0.004	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations	1	1427.5×	0.004	ATRX
Ion influx/efflux at host-pathogen interface	1	713.8×	0.006	ATP7A
Diseases of mitotic cell cycle	1	98.5×	0.031	ATRX
Telomere Maintenance	1	92.1×	0.031	ATRX
Detoxification of Reactive Oxygen Species	1	75.1×	0.031	ATP7A
Association of TriC/CCT with target proteins during biosynthesis	1	73.2×	0.031	GBA1
Glycosphingolipid catabolism	1	73.2×	0.031	GBA1
Antimicrobial peptides	1	56.0×	0.034	ATP7A
Chromosome Maintenance	1	52.9×	0.034	ATRX
Ion transport by P-type ATPases	1	51.9×	0.034	ATP7A
Post-translational modification: synthesis of GPI-anchored proteins	1	42.0×	0.037	ALPL
Inhibition of DNA recombination at telomere	1	42.0×	0.037	ATRX
Cellular response to chemical stress	1	35.7×	0.041	ATP7A
Ion channel transport	1	24.0×	0.057	ATP7A
Cellular responses to stress	1	9.2×	0.133	ATP7A
Cell Cycle	1	9.0×	0.133	ATRX
Cellular responses to stimuli	1	7.9×	0.144	ATP7A
Innate Immune System	1	6.4×	0.163	ATP7A
Transport of small molecules	1	6.3×	0.163	ATP7A
Disease	1	3.3×	0.275	ATRX
Immune System	1	3.2×	0.275	ATP7A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyridoxal 5’-phosphate metabolic process	1	4213.0×	0.006	ALPL
positive regulation of neuronal action potential	1	4213.0×	0.006	GBA1
cerebellar Purkinje cell layer formation	1	2106.5×	0.006	GBA1
response to vitamin B6	1	2106.5×	0.006	ALPL
post-embryonic forelimb morphogenesis	1	2106.5×	0.006	ATRX
obsolete negative regulation of catecholamine metabolic process	1	2106.5×	0.006	ATP7A
futile creatine cycle	1	2106.5×	0.006	ALPL
beta-glucoside catabolic process	1	2106.5×	0.006	GBA1
negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric	1	2106.5×	0.006	ATRX
obsolete L-tryptophan metabolic process	1	1404.3×	0.006	ATP7A
glucosylceramide catabolic process	1	1404.3×	0.006	GBA1
termination of signal transduction	1	1404.3×	0.006	GBA1
epinephrine metabolic process	1	1404.3×	0.006	ATP7A
copper ion export	1	1404.3×	0.006	ATP7A
regulation of lysosomal protein catabolic process	1	1404.3×	0.006	GBA1
neuron apoptotic process	2	92.6×	0.006	GBA1, ATP7A
negative regulation of neuron apoptotic process	2	55.4×	0.006	GBA1, ATP7A
obsolete tyrosine metabolic process	1	1053.2×	0.006	ATP7A
catecholamine metabolic process	1	1053.2×	0.006	ATP7A
response to macrophage colony-stimulating factor	1	1053.2×	0.006	ALPL
inhibition of non-skeletal tissue mineralization	1	1053.2×	0.006	ALPL
developmental process involved in reproduction	1	842.6×	0.006	ALPL
pyramidal neuron differentiation	1	842.6×	0.006	GBA1
T-helper cell differentiation	1	842.6×	0.006	ATP7A
chromosome organization involved in meiotic cell cycle	1	842.6×	0.006	ATRX
autophagosome organization	1	842.6×	0.006	GBA1
response to pH	1	702.2×	0.007	GBA1
positive regulation of nuclear cell cycle DNA replication	1	702.2×	0.007	ATRX
meiotic spindle organization	1	601.9×	0.007	ATRX
copper ion import	1	601.9×	0.007	ATP7A

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
GBA1	MIGALASTAT
ALPL	SULCONAZOLE NITRATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GBA1	12	4
ALPL	7	4
ATRX	0	0
ATP7A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGALASTAT	4	GBA1
GLUCONOLACTONE	4	GBA1
MIGLITOL	4	GBA1
MEXILETINE	4	GBA1
GENTIAN VIOLET	4	GBA1
CHLORHEXIDINE	4	GBA1
TAMOXIFEN	4	GBA1
SULCONAZOLE NITRATE	4	ALPL
THEOPHYLLINE	4	ALPL
LEVAMISOLE	4	ALPL
MICONAZOLE NITRATE	4	ALPL
LEVAMISOLE HYDROCHLORIDE	4	ALPL
AMBROXOL	3	GBA1
AFEGOSTAT	2	GBA1
AFEGOSTAT TARTRATE	2	GBA1
DUVOGLUSTAT	2	GBA1
NIZUBAGLUSTAT	2	GBA1
ISOQUERCETIN	2	ALPL
(-)-EPICATECHIN	2	ALPL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
GBA1	436	Binding:403, Functional:33
ALPL	58	Binding:50, Functional:4, ADMET:3, Toxicity:1
ATP7A	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GBA1	3.2.1.45	glucosylceramidase
ALPL	3.1.3.1	alkaline phosphatase
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GBA1	436

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

19 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	GBA1
GLUCONOLACTONE	4	GBA1
MIGLITOL	4	GBA1
MEXILETINE	4	GBA1
GENTIAN VIOLET	4	GBA1
CHLORHEXIDINE	4	GBA1
TAMOXIFEN	4	GBA1
SULCONAZOLE NITRATE	4	ALPL
THEOPHYLLINE	4	ALPL
LEVAMISOLE	4	ALPL
MICONAZOLE NITRATE	4	ALPL
LEVAMISOLE HYDROCHLORIDE	4	ALPL
AMBROXOL	3	GBA1
AFEGOSTAT	2	GBA1
AFEGOSTAT TARTRATE	2	GBA1
DUVOGLUSTAT	2	GBA1
NIZUBAGLUSTAT	2	GBA1
ISOQUERCETIN	2	ALPL
(-)-EPICATECHIN	2	ALPL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	GBA1, ALPL
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	2	ATRX, ATP7A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATRX	0	—
ATP7A	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.