Leukodystrophy

Summary

Leukodystrophy (MONDO:0019046) is a disease (an umbrella term covering 65 Mondo subtypes) caused by variants in ACER3, LAMB1, and TMEM163, with 32 cohort genes and 8 clinical trials. The dominant Reactome pathway is Glycosphingolipid catabolism (3 cohort genes).

At a glance

• Causal genes: ACER3 (GenCC Strong), LAMB1 (GenCC Strong), TMEM163 (GenCC Strong)
• Umbrella term: 65 Mondo subtypes
• Cohort genes: 32
• ClinVar variants: 74
• Clinical trials: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukodystrophy
Mondo ID	MONDO:0019046
OMIM	312080
Orphanet	68356
DOID	DOID:0050987, DOID:0060786, DOID:10579
ICD-11	468040251
NCIT	C61253
SNOMED CT	192781003
UMLS	C0023520
MedGen	6070
GARD	0006895
MedDRA	10024381
NORD	1367
Is cancer (heuristic)	no

Also known as: hypomyelinating leukodystrophy · hypomyelinating leukoencephalopathy

Data availability: 74 ClinVar variants · 9 GenCC gene-disease records · 5 cell lines.

Disease family

An umbrella term covering 65 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

Subtypes (65): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

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

74 retrieved; paginated sample, class counts are floors:

23 conflicting classifications of pathogenicity, 19 pathogenic/likely pathogenic, 13 uncertain significance, 12 pathogenic, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
374506	NM_001378454.1(ALMS1):c.1732del (p.Arg578fs)	ALMS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3080	NM_000487.6(ARSA):c.1010A>T (p.Asp337Val)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
625852	NM_003676.4(DEGS1):c.764A>G (p.Asn255Ser)	DEGS1	Pathogenic	criteria provided, multiple submitters, no conflicts
598970	NM_003907.3(EIF2B5):c.943C>T (p.Arg315Cys)	EIF2B5	Pathogenic	criteria provided, multiple submitters, no conflicts
134095	NM_000400.4(ERCC2):c.1703_1704del (p.Phe568fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374024	NM_000153.4(GALC):c.850G>A (p.Gly284Ser)	GALC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100729	NM_000520.6(HEXA):c.1305C>T (p.Tyr435=)	HEXA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17558	NM_002156.5(HSPD1):c.86A>G (p.Asp29Gly)	HSPD1	Pathogenic	criteria provided, single submitter
996070	NM_016199.3(LSM7):c.121G>A (p.Asp41Asn)	LSM7	Pathogenic	no assertion criteria provided
1030186	NM_007055.4(POLR3A):c.3733C>T (p.Arg1245Ter)	POLR3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1385211	NM_007055.4(POLR3A):c.1393C>T (p.Gln465Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1429579	NM_007055.4(POLR3A):c.3669C>A (p.Tyr1223Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453734	NM_007055.4(POLR3A):c.147_148insT (p.Pro50fs)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454335	NM_007055.4(POLR3A):c.3688_3691dup (p.Asn1231delinsArgTer)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235466	NM_007055.4(POLR3A):c.2617C>T (p.Arg873Ter)	POLR3A	Pathogenic	criteria provided, multiple submitters, no conflicts
2412670	NM_007055.4(POLR3A):c.3115C>T (p.Gln1039Ter)	POLR3A	Pathogenic	criteria provided, multiple submitters, no conflicts
2412671	NM_007055.4(POLR3A):c.2710G>T (p.Gly904Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280111	NM_007055.4(POLR3A):c.1740dup (p.Val581fs)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31145	NM_007055.4(POLR3A):c.2554A>G (p.Met852Val)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31146	NM_007055.4(POLR3A):c.2617-1G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31149	NM_007055.4(POLR3A):c.3013C>T (p.Arg1005Cys)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
41245	NM_007055.4(POLR3A):c.2830G>T (p.Glu944Ter)	POLR3A	Pathogenic	criteria provided, single submitter
432594	NM_007055.4(POLR3A):c.3337-5T>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
436361	NM_007055.4(POLR3A):c.3243-1G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
986804	NM_007055.4(POLR3A):c.3944_3945del (p.Val1315fs)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988361	NM_007055.4(POLR3A):c.3655G>T (p.Gly1219Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
254247	NM_013328.4(PYCR2):c.796C>T (p.Arg266Ter)	PYCR2	Pathogenic	criteria provided, multiple submitters, no conflicts
689459	NM_014698.3(TMEM63A):c.503G>A (p.Gly168Glu)	TMEM63A	Pathogenic	criteria provided, multiple submitters, no conflicts
689460	NM_014698.3(TMEM63A):c.1385T>A (p.Ile462Asn)	TMEM63A	Pathogenic	criteria provided, single submitter
689461	NM_014698.3(TMEM63A):c.1699G>A (p.Gly567Ser)	TMEM63A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 38 · Orphanet: 55 · 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
ACER3	Strong	Autosomal recessive	leukodystrophy	4
LAMB1	Strong	Autosomal dominant	leukodystrophy	8
TMEM163	Strong	Autosomal dominant	leukodystrophy, hypomyelinating, 25	5
LSM7	Moderate	Autosomal recessive	leukodystrophy
NOTCH1	Moderate	Autosomal dominant	leukodystrophy	9
PLD3	Moderate	Autosomal recessive	leukodystrophy	4
TOMM70	Moderate	Autosomal dominant	leukodystrophy	4
ALDH1L2	Limited	Autosomal recessive	leukodystrophy	2
VPS18	No Known Disease Relationship	Unknown	leukodystrophy

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMB1	Orphanet:352682	Cobblestone lissencephaly without muscular or ocular involvement
ACER3	Orphanet:502444	Alkaline ceramidase 3 deficiency
PLD3	Orphanet:589522	Spinocerebellar ataxia type 46
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome
SCP2	Orphanet:163684	Leukoencephalopathy-dystonia-motor neuropathy syndrome
SLC9A6	Orphanet:85278	Christianson syndrome
TUBB4A	Orphanet:139441	Hypomyelination with atrophy of basal ganglia and cerebellum
TUBB4A	Orphanet:98805	Primary dystonia, DYT4 type
RNF216	Orphanet:1173	Cerebellar ataxia-hypogonadism syndrome
POLR3A	Orphanet:137639	Hypomyelinating leukodystrophy-ataxia-hypodontia-hypomyelination syndrome
POLR3A	Orphanet:3455	Wiedemann-Rautenstrauch syndrome
POLR3A	Orphanet:447893	Hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome
POLR3A	Orphanet:447896	Tremor-ataxia-central hypomyelination syndrome
POLR3A	Orphanet:77295	Odontoleukodystrophy
POLR3A	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
PYCR2	Orphanet:2512	Autosomal recessive primary microcephaly
PYCR2	Orphanet:481152	PYCR2-related microcephaly-progressive leukoencephalopathy
POLR3B	Orphanet:85186	Endosteal sclerosis-cerebellar hypoplasia syndrome
POLR3B	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
EIF2B5	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B5	Orphanet:157716	Late infantile CACH syndrome
EIF2B5	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B5	Orphanet:99853	Ovarioleukodystrophy
EIF2B5	Orphanet:99854	Cree leukoencephalopathy
ERCC2	Orphanet:1466	COFS syndrome
ERCC2	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC2	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:910	Xeroderma pigmentosum
GALC	Orphanet:206436	Infantile Krabbe disease
GALC	Orphanet:206443	Late-infantile/juvenile Krabbe disease
GALC	Orphanet:206448	Adult Krabbe disease
ALMS1	Orphanet:64	Alström syndrome
HEXA	Orphanet:309178	Tay-Sachs disease, infantile form
HEXA	Orphanet:309185	Tay-Sachs disease, juvenile form
HEXA	Orphanet:309192	Tay-Sachs disease, adult form
HSPD1	Orphanet:100994	Autosomal dominant spastic paraplegia type 13
HSPD1	Orphanet:280288	Pelizaeus-Merzbacher-like disease due to HSPD1 mutation
KARS1	Orphanet:254334	Autosomal recessive intermediate Charcot-Marie-Tooth disease type B
KARS1	Orphanet:3240	Early-onset progressive leukoencephalopathy-central nervous system calcification-deafness-visual impairment syndrome
KARS1	Orphanet:652532	Adult-onset progressive leukoencephalopathy-early-onset deafness
KARS1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
ARSA	Orphanet:309256	Metachromatic leukodystrophy, late infantile form
ARSA	Orphanet:309263	Metachromatic leukodystrophy, juvenile form
ARSA	Orphanet:309271	Metachromatic leukodystrophy, adult form
AIFM1	Orphanet:101078	X-linked Charcot-Marie-Tooth disease type 4
AIFM1	Orphanet:139583	X-linked hereditary sensory and autonomic neuropathy with deafness
AIFM1	Orphanet:238329	Severe X-linked mitochondrial encephalomyopathy
AIFM1	Orphanet:83629	Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome
PEX6	Orphanet:3220	Deafness-enamel hypoplasia-nail defects syndrome

Cohort genes → proteins

32 cohort genes, 32 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	32

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LSM7	HGNC:20470	ENSG00000130332	Q9UK45	U6 snRNA-associated Sm-like protein LSm7	gencc,clinvar
LAMB1	HGNC:6486	ENSG00000091136	P07942	Laminin subunit beta-1	gencc,clinvar
TOMM70	HGNC:11985	ENSG00000154174	O94826	Mitochondrial import receptor subunit TOM70	gencc
VPS18	HGNC:15972	ENSG00000104142	Q9P253	Vacuolar protein sorting-associated protein 18 homolog	gencc
ACER3	HGNC:16066	ENSG00000078124	Q9NUN7	Alkaline ceramidase 3	gencc
PLD3	HGNC:17158	ENSG00000105223	Q8IV08	5’-3’ exonuclease PLD3	gencc
TMEM163	HGNC:25380	ENSG00000152128	Q8TC26	Transmembrane protein 163	gencc
ALDH1L2	HGNC:26777	ENSG00000136010	Q3SY69	Mitochondrial 10-formyltetrahydrofolate dehydrogenase	gencc
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	gencc
SCP2	HGNC:10606	ENSG00000116171	P22307	Sterol carrier protein 2	clinvar
SLC9A6	HGNC:11079	ENSG00000198689	Q92581	Sodium/hydrogen exchanger 6	clinvar
DEGS1	HGNC:13709	ENSG00000143753	O15121	Sphingolipid delta(4)-desaturase DES1	clinvar
CTDSP2	HGNC:17077	ENSG00000175215	O14595	Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2	clinvar
TUBB4A	HGNC:20774	ENSG00000104833	P04350	Tubulin beta-4A chain	clinvar
RNF216	HGNC:21698	ENSG00000011275	Q9NWF9	E3 ubiquitin-protein ligase RNF216	clinvar
U2AF2	HGNC:23156	ENSG00000063244	P26368	Splicing factor U2AF 65 kDa subunit	clinvar
RNF182	HGNC:28522	ENSG00000180537	Q8N6D2	E3 ubiquitin-protein ligase RNF182	clinvar
TMEM63A	HGNC:29118	ENSG00000196187	O94886	Mechanosensitive cation channel TMEM63A	clinvar
POLR3A	HGNC:30074	ENSG00000148606	O14802	DNA-directed RNA polymerase III subunit RPC1	clinvar
PYCR2	HGNC:30262	ENSG00000143811	Q96C36	Pyrroline-5-carboxylate reductase 2	clinvar
POLR3B	HGNC:30348	ENSG00000013503	Q9NW08	DNA-directed RNA polymerase III subunit RPC2	clinvar
EIF2B5	HGNC:3261	ENSG00000145191	Q13144	Translation initiation factor eIF2B subunit epsilon	clinvar
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	clinvar
GALC	HGNC:4115	ENSG00000054983	P54803	Galactocerebrosidase	clinvar
ALMS1	HGNC:428	ENSG00000116127	Q8TCU4	Centrosome-associated protein ALMS1	clinvar
HEXA	HGNC:4878	ENSG00000213614	P06865	Beta-hexosaminidase subunit alpha	clinvar
HSPD1	HGNC:5261	ENSG00000144381	P10809	60 kDa heat shock protein, mitochondrial	clinvar
KARS1	HGNC:6215	ENSG00000065427	Q15046	Lysine–tRNA ligase	clinvar
ARSA	HGNC:713	ENSG00000100299	P15289	Arylsulfatase A	clinvar
AIFM1	HGNC:8768	ENSG00000156709	O95831	Apoptosis-inducing factor 1, mitochondrial	clinvar
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	clinvar
RARS1	HGNC:9870	ENSG00000113643	P54136	Arginine–tRNA ligase, cytoplasmic	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LSM7	U6 snRNA-associated Sm-like protein LSm7	Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex).
LAMB1	Laminin subunit beta-1	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
TOMM70	Mitochondrial import receptor subunit TOM70	Acts as a receptor of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex).
VPS18	Vacuolar protein sorting-associated protein 18 homolog	Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways.
ACER3	Alkaline ceramidase 3	Endoplasmic reticulum and Golgi ceramidase that catalyzes the hydrolysis of unsaturated long-chain C18:1-, C20:1- and C20:4-ceramides, dihydroceramides and phytoceramides into sphingoid bases like sphingosine and free fatty acids at alkali…
PLD3	5’-3’ exonuclease PLD3	5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments.
TMEM163	Transmembrane protein 163	Zinc ion transporter that mediates zinc efflux and plays a crucial role in intracellular zinc homeostasis.
ALDH1L2	Mitochondrial 10-formyltetrahydrofolate dehydrogenase	Mitochondrial 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.
SCP2	Sterol carrier protein 2	Plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids.
SLC9A6	Sodium/hydrogen exchanger 6	Endosomal Na(+), K(+)/H(+) antiporter.
DEGS1	Sphingolipid delta(4)-desaturase DES1	Has sphingolipid-delta-4-desaturase activity.
CTDSP2	Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2	Preferentially catalyzes the dephosphorylation of ‘Ser-5’ within the tandem 7 residue repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A.
TUBB4A	Tubulin beta-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
RNF216	E3 ubiquitin-protein ligase RNF216	E3 ubiquitin ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their ubiquitination.
U2AF2	Splicing factor U2AF 65 kDa subunit	Plays a role in pre-mRNA splicing and 3’-end processing.
RNF182	E3 ubiquitin-protein ligase RNF182	E3 ubiquitin-protein ligase that mediates the ubiquitination of ATP6V0C and targets it to degradation via the ubiquitin-proteasome pathway.
TMEM63A	Mechanosensitive cation channel TMEM63A	Mechanosensitive cation channel with low conductance and high activation threshold.
POLR3A	DNA-directed RNA polymerase III subunit RPC1	Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates.
PYCR2	Pyrroline-5-carboxylate reductase 2	Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5-carboxylate to L-proline using NAD(P)H.
POLR3B	DNA-directed RNA polymerase III subunit RPC2	Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates.
EIF2B5	Translation initiation factor eIF2B subunit epsilon	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
GALC	Galactocerebrosidase	Hydrolyzes the galactose ester bonds of glycolipids such as galactosylceramide and galactosylsphingosine.
ALMS1	Centrosome-associated protein ALMS1	Involved in PCM1-dependent intracellular transport.
HEXA	Beta-hexosaminidase subunit alpha	Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides.
HSPD1	60 kDa heat shock protein, mitochondrial	Chaperonin implicated in mitochondrial protein import and macromolecular assembly.
KARS1	Lysine–tRNA ligase	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
ARSA	Arylsulfatase A	Hydrolyzes cerebroside sulfate.
AIFM1	Apoptosis-inducing factor 1, mitochondrial	Functions both as NADH oxidoreductase and as regulator of apoptosis.
PEX6	Peroxisomal ATPase PEX6	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.
RARS1	Arginine–tRNA ligase, cytoplasmic	Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis.

Protein-family classification

Druggable: 14 · Difficult: 3 · Unknown: 15 · Druggable fraction: 0.44

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)	11	4.1×	2e-04
Phosphatase	2	5.2×	0.167
Other/Unknown	15	0.8×	0.913
GPCR	1	0.8×	0.913
Scaffold/PPI	1	0.5×	0.913
Transcription factor	2	0.5×	0.913

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LSM7	Other/Unknown	no		Sm_dom_euk/arc, LSM_dom_sf, Lsm7
LAMB1	Other/Unknown	no		EGF, LE_dom, Laminin_N
TOMM70	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt
VPS18	Other/Unknown	no		Clathrin_H-chain/VPS_repeat, Pep3/Vps18_beta-prop, Pep3/Vps18_RING_C
ACER3	Enzyme (other)	yes	3.5.1.23	ACER
PLD3	Other/Unknown	no		PLipase_D/transphosphatidylase, PLDc_3, Diverse_PLD-related
TMEM163	Other/Unknown	no		Tmem163, Cation_efflux_TMD_sf
ALDH1L2	Enzyme (other)	yes	1.5.1.6	GART_AS, Formyl_transf_N, Formyl_trans_C
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
SCP2	Enzyme (other)	yes	2.3.1.176	SCP2_sterol-bd_dom, Thiolase-like, Thiolase_CS
SLC9A6	Other/Unknown	no		NHE-6/7/9, NaH_exchanger, Cation/H_exchanger_TM
DEGS1	Enzyme (other)	yes	1.14.19.17	FA_desaturase_dom, DES1/DES2, Sphingolipid_d4-desaturase_N
CTDSP2	Phosphatase	yes		FCP1_dom, Dullard_phosphatase, HAD_sf
TUBB4A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
RNF216	Transcription factor	no		IBR_dom, Znf_RING/FYVE/PHD, TRIAD_supradom
U2AF2	Other/Unknown	no		RRM_dom, U2AF_lg, Nucleotide-bd_a/b_plait_sf
RNF182	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
TMEM63A	GPCR	yes		CSC1/OSCA1-like_7TM, Nucleotide-bd_a/b_plait_sf, CSC1/OSCA1-like_cyt
POLR3A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3
PYCR2	Other/Unknown	no		Pyrroline-COOH_reductase, 6-PGluconate_DH-like_C_sf, P5C_Rdtase_cat_N
POLR3B	Other/Unknown	no		DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7
EIF2B5	Other/Unknown	no		W2_domain, Trimer_LpxA-like_sf, ARM-type_fold
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
GALC	Enzyme (other)	yes	3.2.1.46	Glyco_hydro_59, Aldolase_TIM, GH_hydrolase_sf
ALMS1	Other/Unknown	no		ALMS_motif, ALMS_repeat
HEXA	Enzyme (other)	yes	3.2.1.169	GH20_cat, GH_hydrolase_sf, GH20
HSPD1	Other/Unknown	no		Cpn60/GroEL, Cpn60/GroEL/TCP-1, Chaperonin_Cpn60_CS
KARS1	Enzyme (other)	yes	6.1.1.6	Lys-tRNA-ligase_II, Aa-tRNA-synt_II, NA-bd_OB_tRNA
ARSA	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
AIFM1	Enzyme (other)	yes	7.1.1.2	FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
RARS1	Enzyme (other)	yes	6.1.1.19	Arg-tRNA-ligase, aa-tRNA-synth_I_CS, Arg-tRNA-synth_N

Expression context

Cohort genes with no expression data: 0.

30 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)	32
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	5
endothelial cell	4
stromal cell of endometrium	4
granulocyte	3
secondary oocyte	3
esophagus squamous epithelium	3
jejunal mucosa	3
ganglionic eminence	2
mucosa of transverse colon	2
tendon of biceps brachii	2
lateral nuclear group of thalamus	2
body of pancreas	2
middle temporal gyrus	2
right testis	2
buccal mucosa cell	2
right adrenal gland	2
adrenal tissue	2
nerve	1
omental fat pad	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LSM7	287	ubiquitous	marker	mucosa of transverse colon, granulocyte, ganglionic eminence
LAMB1	284	ubiquitous	marker	nerve, tibial nerve, omental fat pad
TOMM70	299	ubiquitous	marker	endothelial cell, gluteal muscle, Brodmann (1909) area 23
VPS18	233	ubiquitous	marker	pancreatic ductal cell, tendon of biceps brachii, kidney epithelium
ACER3	252	ubiquitous	marker	endothelial cell, inferior vagus X ganglion, ileal mucosa
PLD3	282	ubiquitous	marker	adenohypophysis, pituitary gland, right frontal lobe
TMEM163	201	broad	marker	oocyte, secondary oocyte, lateral nuclear group of thalamus
ALDH1L2	224	ubiquitous	marker	tibia, body of pancreas, stromal cell of endometrium
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura
SCP2	295	ubiquitous	marker	jejunal mucosa, esophagus squamous epithelium, right lobe of liver
SLC9A6	286	ubiquitous	yes	lateral nuclear group of thalamus, middle temporal gyrus, pons
DEGS1	293	ubiquitous	marker	skin of hip, upper leg skin, penis
CTDSP2	295	ubiquitous	marker	mucosa of stomach, stromal cell of endometrium, descending thoracic aorta
TUBB4A	201	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
RNF216	278	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
U2AF2	288	ubiquitous	marker	right uterine tube, endocervix, granulocyte
RNF182	192	broad	yes	endothelial cell, cortical plate, ganglionic eminence
TMEM63A	271	ubiquitous	marker	C1 segment of cervical spinal cord, right uterine tube, middle frontal gyrus
POLR3A	242	ubiquitous	marker	buccal mucosa cell, middle temporal gyrus, secondary oocyte
PYCR2	251	ubiquitous	marker	cardiac muscle of right atrium, right uterine tube, left ventricle myocardium
POLR3B	247	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, endothelial cell
EIF2B5	286	ubiquitous	marker	sural nerve, tendon of biceps brachii, gastrocnemius
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
GALC	295	ubiquitous	marker	adrenal tissue, bronchial epithelial cell, jejunal mucosa
ALMS1	275	ubiquitous	marker	buccal mucosa cell, periodontal ligament, cardia of stomach
HEXA	293	ubiquitous	marker	type B pancreatic cell, gall bladder, stromal cell of endometrium
HSPD1	217	ubiquitous	marker	adrenal tissue, right adrenal gland, right adrenal gland cortex
KARS1	299	ubiquitous	marker	gingival epithelium, parietal pleura, endometrium epithelium
ARSA	177	ubiquitous	marker	right uterine tube, right testis, granulocyte
AIFM1	273	ubiquitous	marker	apex of heart, adult mammalian kidney, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPD1	7,876
NOTCH1	7,411
POLR3B	5,712
TUBB4A	5,138
U2AF2	5,003
POLR3A	4,915
AIFM1	4,780
KARS1	4,681
RARS1	4,094
EIF2B5	2,989

Intra-cohort edges

A	B	Sources
AIFM1	PYCR2	intact
ARSA	GALC	string_interaction
KARS1	RARS1	string_interaction
POLR3A	POLR3B	string_interaction
POLR3A	PYCR2	string_interaction
POLR3A	RNF216	string_interaction
PYCR2	TMEM63A	string_interaction

Structural data

PDB: 22 · AlphaFold-only: 10 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC2	P18074	51
U2AF2	P26368	40
HSPD1	P10809	31
NOTCH1	P46531	29
POLR3A	O14802	29
POLR3B	Q9NW08	29
EIF2B5	Q13144	26
AIFM1	O95831	26
LSM7	Q9UK45	20
KARS1	Q15046	14
ARSA	P15289	10
PLD3	Q8IV08	7
TMEM63A	O94886	6
RARS1	P54136	5
RNF216	Q9NWF9	4
LAMB1	P07942	3
TOMM70	O94826	3
ACER3	Q9NUN7	2
SCP2	P22307	2
PYCR2	Q96C36	2
HEXA	P06865	2
CTDSP2	O14595	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DEGS1	O15121	96.93
GALC	P54803	94.56
ALDH1L2	Q3SY69	92.71
TUBB4A	P04350	92.25
VPS18	Q9P253	79.32
TMEM163	Q8TC26	76.65
RNF182	Q8N6D2	70.67
SLC9A6	Q92581	70.61
PEX6	Q13608	69.87
ALMS1	Q8TCU4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 241. Enrichment computed across 32 evidence-associated genes (30 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 30 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid catabolism	3	29.3×	0.034	GALC, HEXA, ARSA
Defective HEXA causes GM2G1 (Hyaluronan metabolism)	1	380.7×	0.070	HEXA
Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH)	1	380.7×	0.070	SLC9A6
RNA Polymerase III Chain Elongation	2	42.3×	0.070	POLR3A, POLR3B
RNA Polymerase III Transcription Termination	2	33.1×	0.070	POLR3A, POLR3B
Cytosolic tRNA aminoacylation	2	29.3×	0.070	KARS1, RARS1
RNA Polymerase III Transcription Initiation From Type 2 Promoter	2	28.2×	0.070	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation From Type 1 Promoter	2	27.2×	0.070	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation From Type 3 Promoter	2	27.2×	0.070	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation	2	22.4×	0.082	POLR3A, POLR3B
RNA Polymerase III Transcription	2	21.8×	0.082	POLR3A, POLR3B
Cytosolic sensors of pathogen-associated DNA	2	19.0×	0.088	POLR3A, POLR3B
tRNA Aminoacylation	2	19.0×	0.088	KARS1, RARS1
RNA Polymerase III Abortive And Retractive Initiation	2	18.6×	0.088	POLR3A, POLR3B
DDX58/IFIH1-mediated induction of interferon-alpha/beta	2	16.9×	0.093	TOMM70, RNF216
Centrosome maturation	2	16.9×	0.093	TUBB4A, ALMS1
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	76.1×	0.135	NOTCH1
Defective LFNG causes SCDO3	1	76.1×	0.135	NOTCH1
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	76.1×	0.135	HSPD1
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	63.4×	0.135	NOTCH1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	63.4×	0.135	SCP2
Selenoamino acid metabolism	2	13.1×	0.135	KARS1, RARS1
Transcriptional and post-translational regulation of MITF-M expression and activity	2	11.9×	0.135	KARS1, RARS1
Peroxisomal protein import	2	11.5×	0.135	SCP2, PEX6
Mitochondrial protein import	2	11.2×	0.135	TOMM70, HSPD1
Sphingolipid metabolism	2	11.2×	0.135	ACER3, ARSA
Loss of Nlp from mitotic centrosomes	2	10.6×	0.135	TUBB4A, ALMS1
Loss of proteins required for interphase microtubule organization from the centrosome	2	10.6×	0.135	TUBB4A, ALMS1
AURKA Activation by TPX2	2	10.2×	0.137	TUBB4A, ALMS1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	54.4×	0.145	NOTCH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 32 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
myelination	5	39.3×	6e-05	ACER3, TMEM163, EIF2B5, GALC, HEXA
protein import into mitochondrial intermembrane space	2	351.1×	0.002	HSPD1, AIFM1
positive regulation of interferon-beta production	3	36.7×	0.010	TOMM70, POLR3A, POLR3B
lysosome organization	3	28.7×	0.015	VPS18, TMEM63A, HEXA
coronary sinus valve morphogenesis	1	526.6×	0.040	NOTCH1
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	526.6×	0.040	NOTCH1
lysyl-tRNA aminoacylation	1	526.6×	0.040	KARS1
foregut morphogenesis	1	526.6×	0.040	NOTCH1
neuronal-glial interaction involved in cerebral cortex radial glia guided migration	1	526.6×	0.040	LAMB1
positive regulation of intracellular cholesterol transport	1	526.6×	0.040	SCP2
positive regulation of steroid metabolic process	1	526.6×	0.040	SCP2
isotype switching to IgG isotypes	1	526.6×	0.040	HSPD1
regulation of epithelial cell proliferation involved in prostate gland development	1	526.6×	0.040	NOTCH1
venous endothelial cell differentiation	1	526.6×	0.040	NOTCH1
phytosphingosine biosynthetic process	1	526.6×	0.040	ACER3
basophil activation involved in immune response	1	263.3×	0.040	KARS1
endocardium morphogenesis	1	263.3×	0.040	NOTCH1
coronary vein morphogenesis	1	263.3×	0.040	NOTCH1
cardiac right atrium morphogenesis	1	263.3×	0.040	NOTCH1
growth involved in heart morphogenesis	1	263.3×	0.040	NOTCH1
obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	1	263.3×	0.040	NOTCH1
galactosylceramide catabolic process	1	263.3×	0.040	GALC
cell differentiation in spinal cord	1	263.3×	0.040	NOTCH1
mitochondrial unfolded protein response	1	263.3×	0.040	HSPD1
positive regulation of mitotic recombination	1	263.3×	0.040	ERCC2
regulation of phospholipid biosynthetic process	1	263.3×	0.040	SCP2
zinc ion import into synaptic vesicle	1	263.3×	0.040	TMEM163
surfactant secretion	1	263.3×	0.040	TMEM63A
lipid hydroperoxide transport	1	263.3×	0.040	SCP2
positive regulation of aorta morphogenesis	1	263.3×	0.040	NOTCH1

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 6 · Phased (≥1): 10 · Undrugged: 22

Druggability breadth: 20 of 32 evidence-associated genes (62%) 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
TUBB4A	COLCHICINE
ERCC2	SUNITINIB
HEXA	PYRIMETHAMINE
HSPD1	CHOLECALCIFEROL
KARS1	IMATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HSPD1	27	4
TUBB4A	21	4
ERCC2	16	4
NOTCH1	1	2
DEGS1	1	3
U2AF2	1	2
EIF2B5	1	2
HEXA	1	4
KARS1	1	4
RARS1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
SUNITINIB	4	ERCC2
PYRIMETHAMINE	4	HEXA
CHOLECALCIFEROL	4	HSPD1
EVANS BLUE	4	HSPD1
PHENOXYBENZAMINE HYDROCHLORIDE	4	HSPD1
ADAPALENE	4	HSPD1
ERGOCALCIFEROL	4	HSPD1
METABROMSALAN	4	HSPD1
BITHIONOL	4	HSPD1
TRETINOIN	4	HSPD1
BENZBROMARONE	4	HSPD1
RIBOFLAVIN 5’-PHOSPHATE SODIUM	4	HSPD1
ETHACRYNIC ACID	4	HSPD1
HEXACHLOROPHENE	4	HSPD1
TANNIC ACID	4	HSPD1
MENADIONE	4	HSPD1
IVERMECTIN	4	HSPD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 11.

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

Symbol	Assays	Type breakdown
TUBB4A	1,758	Binding:1718, Functional:34, ADMET:6
HEXA	58	Binding:58
KARS1	46	Binding:45, ADMET:1
NOTCH1	23	Binding:19, ADMET:4
HSPD1	22	Binding:18, ADMET:2, Functional:2
DEGS1	17	Binding:15, ADMET:2
PLD3	13	Binding:13
RARS1	10	Binding:10
U2AF2	8	Binding:8
EIF2B5	7	Binding:7
SCP2	4	Binding:4
ARSA	4	Binding:3, Functional:1
ERCC2	3	Binding:3
GALC	3	Binding:2, Functional:1
TOMM70	2	Binding:2
PYCR2	2	Binding:2
AIFM1	2	Binding:2
LAMB1	1	Binding:1
TMEM63A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACER3	3.5.1.23	ceramidase
ALDH1L2	1.5.1.6	formyltetrahydrofolate dehydrogenase
SCP2	2.3.1.176	propanoyl-CoA C-acyltransferase
DEGS1	1.14.19.17	sphingolipid 4-desaturase
ERCC2	3.6.4.12	DNA helicase
GALC	3.2.1.46	galactosylceramidase
HEXA	3.2.1.169	protein O-GlcNAcase
KARS1	6.1.1.6	lysine-tRNA ligase
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)
PEX6	3.6.4.7	peroxisome-assembly ATPase
RARS1	6.1.1.19	arginine-tRNA ligase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBB4A	1,758

Pharmacogenomics

Cohort genes with a PharmGKB record: 32; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
SUNITINIB	4	ERCC2
PYRIMETHAMINE	4	HEXA
CHOLECALCIFEROL	4	HSPD1
EVANS BLUE	4	HSPD1
PHENOXYBENZAMINE HYDROCHLORIDE	4	HSPD1
ADAPALENE	4	HSPD1
ERGOCALCIFEROL	4	HSPD1
METABROMSALAN	4	HSPD1
BITHIONOL	4	HSPD1
TRETINOIN	4	HSPD1
BENZBROMARONE	4	HSPD1
RIBOFLAVIN 5’-PHOSPHATE SODIUM	4	HSPD1
ETHACRYNIC ACID	4	HSPD1
HEXACHLOROPHENE	4	HSPD1
TANNIC ACID	4	HSPD1
MENADIONE	4	HSPD1
IVERMECTIN	4	HSPD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	TUBB4A, ERCC2, HEXA, HSPD1, KARS1
B	Phased (≥1) drug, not yet approved	5	NOTCH1, DEGS1, U2AF2, EIF2B5, RARS1
C	Druggable family + PDB, no drug	6	ACER3, SCP2, CTDSP2, TMEM63A, ARSA, AIFM1
D	Druggable family + AlphaFold only, no drug	3	ALDH1L2, GALC, PEX6
E	Difficult family or no structure, no drug	13	LSM7, LAMB1, TOMM70, VPS18, PLD3, TMEM163, SLC9A6, RNF216, RNF182, POLR3A (+3 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LSM7	0	—
LAMB1	1	—
TOMM70	2	—
VPS18	0	—
ACER3	0	—
PLD3	13	—
TMEM163	0	—
ALDH1L2	0	—
SCP2	4	—
SLC9A6	0	—
CTDSP2	0	—
RNF216	0	—
RNF182	0	—
TMEM63A	1	—
POLR3A	0	—
PYCR2	2	—
POLR3B	0	—
GALC	3	—
ALMS1	0	—
ARSA	4	—
AIFM1	2	—
PEX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies