Juvenile amyotrophic lateral sclerosis

disease

On this page

Also known as amyotrophic lateral sclerosis, juvenileJALSjuvenile Charcot diseasejuvenile Lou Gehrig disease

Summary

Juvenile amyotrophic lateral sclerosis (MONDO:0017593) is a disease with 9 cohort genes.

At a glance

Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
Cohort genes: 9
ClinVar variants: 15
Phenotypes (HPO): 46

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003693	Distal amyotrophy	Very frequent (80-99%)
HP:0006986	Upper limb spasticity	Very frequent (80-99%)
HP:0007354	Amyotrophic lateral sclerosis	Very frequent (80-99%)
HP:0001264	Spastic diplegia	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002483	Bulbar signs	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0003429	CNS hypomyelination	Frequent (30-79%)
HP:0005750	Contractures of the joints of the lower limbs	Frequent (30-79%)
HP:0031936	Delayed ability to walk	Frequent (30-79%)
HP:0031960	Arm dystonia	Frequent (30-79%)
HP:0100295	Muscle fiber atrophy	Frequent (30-79%)
HP:0100360	Contractures of the joints of the upper limbs	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000605	Supranuclear gaze palsy	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002169	Clonus	Occasional (5-29%)
HP:0002179	Opisthotonus	Occasional (5-29%)
HP:0002425	Anarthria	Occasional (5-29%)
HP:0002530	Axial dystonia	Occasional (5-29%)
HP:0002544	Retrocollis	Occasional (5-29%)
HP:0002599	Head titubation	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003701	Proximal muscle weakness	Occasional (5-29%)
HP:0003722	Neck flexor weakness	Occasional (5-29%)
HP:0004326	Cachexia	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0012048	Oromandibular dystonia	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	juvenile amyotrophic lateral sclerosis
Mondo ID	MONDO:0017593
Orphanet	300605
SNOMED CT	718555006
UMLS	C3468114
MedGen	923704
GARD	0011901
Is cancer (heuristic)	no

Also known as: amyotrophic lateral sclerosis, juvenile · JALS · juvenile Charcot disease · juvenile Lou Gehrig disease

Data availability: 15 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › juvenile amyotrophic lateral sclerosis

Subtypes (4): amyotrophic lateral sclerosis type 2, juvenile, juvenile amyotrophic lateral sclerosis with dementia, amyotrophic lateral sclerosis type 5, amyotrophic lateral sclerosis type 16

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

15 retrieved; paginated sample, class counts are floors:

8 pathogenic, 3 uncertain significance, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1679834	NM_020919.4(ALS2):c.4270C>T (p.Gln1424Ter)	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
873226	NM_006459.4(ERLIN1):c.281T>C (p.Val94Ala)	ERLIN1	Pathogenic	criteria provided, single submitter
280110	NM_004960.4(FUS):c.1574C>T (p.Pro525Leu)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
873234	NM_004960.4(FUS):c.1577A>G (p.Tyr526Cys)	FUS	Pathogenic	criteria provided, single submitter
873314	NM_020631.6(PLEKHG5):c.1417C>T (p.Gln473Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
1072015	NM_025137.4(SPG11):c.4432C>T (p.Gln1478Ter)	SPG11	Pathogenic	criteria provided, single submitter
374112	NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
873270	NM_182961.4(SYNE1):c.22930C>T (p.Gln7644Ter)	SYNE1	Pathogenic	criteria provided, single submitter
873271	NM_182961.4(SYNE1):c.23524C>T (p.Arg7842Ter)	SYNE1	Pathogenic	criteria provided, multiple submitters, no conflicts
209205	NM_003384.3(VRK1):c.961C>T (p.Arg321Cys)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
873315	NM_020631.6(PLEKHG5):c.1889C>A (p.Pro630His)	PLEKHG5	Likely pathogenic	criteria provided, single submitter
4807	NM_017672.6(TRPM7):c.4445C>T (p.Thr1482Ile)	TRPM7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024648	NM_025137.4(SPG11):c.4402C>G (p.Pro1468Ala)	SPG11	Uncertain significance	criteria provided, single submitter
566874	NM_025137.4(SPG11):c.4365G>C (p.Trp1455Cys)	SPG11	Uncertain significance	criteria provided, multiple submitters, no conflicts
664720	NM_025137.4(SPG11):c.5990T>A (p.Leu1997Gln)	SPG11	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · Orphanet: 23 · 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
FUS	Definitive	Autosomal dominant	amyotrophic lateral sclerosis	7
ALS2	Strong	Autosomal recessive	amyotrophic lateral sclerosis type 2, juvenile	10
SIGMAR1	Strong	Autosomal recessive	amyotrophic lateral sclerosis type 16	6
SPG11	Strong	Autosomal recessive	amyotrophic lateral sclerosis type 5	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPG11	Orphanet:2822	Autosomal recessive spastic paraplegia type 11
SPG11	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPG11	Orphanet:466775	Autosomal recessive Charcot-Marie-Tooth disease type 2X
FUS	Orphanet:275872	Frontotemporal dementia with motor neuron disease
FUS	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
FUS	Orphanet:79105	Myxofibrosarcoma
FUS	Orphanet:803	Amyotrophic lateral sclerosis
FUS	Orphanet:99967	Myxoid/round cell liposarcoma
ALS2	Orphanet:247604	Juvenile primary lateral sclerosis
ALS2	Orphanet:293168	Infantile-onset ascending hereditary spastic paralysis
ALS2	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SIGMAR1	Orphanet:139552	Distal hereditary motor neuropathy, Jerash type
SIGMAR1	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
VRK1	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:423894	Microcephaly-complex motor and sensory axonal neuropathy syndrome
ERLIN1	Orphanet:401785	Autosomal recessive spastic paraplegia type 62
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
TRPM7	Orphanet:140957	Autosomal dominant macrothrombocytopenia
TRPM7	Orphanet:90020	Parkinson-dementia complex of Guam
PLEKHG5	Orphanet:206580	Autosomal recessive lower motor neuron disease with childhood onset
PLEKHG5	Orphanet:369867	Autosomal recessive intermediate Charcot-Marie-Tooth disease type C

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPG11	HGNC:11226	ENSG00000104133	Q96JI7	Spatacsin	gencc,clinvar
FUS	HGNC:4010	ENSG00000089280	P35637	RNA-binding protein FUS	gencc,clinvar
ALS2	HGNC:443	ENSG00000003393	Q96Q42	Alsin	gencc,clinvar
SIGMAR1	HGNC:8157	ENSG00000147955	Q99720	Sigma non-opioid intracellular receptor 1	gencc
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	clinvar
ERLIN1	HGNC:16947	ENSG00000107566	O75477	Erlin-1	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
TRPM7	HGNC:17994	ENSG00000092439	Q96QT4	Transient receptor potential cation channel subfamily M member 7	clinvar
PLEKHG5	HGNC:29105	ENSG00000171680	O94827	Pleckstrin homology domain-containing family G member 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPG11	Spatacsin	May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
FUS	RNA-binding protein FUS	DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response.
ALS2	Alsin	May act as a GTPase regulator.
SIGMAR1	Sigma non-opioid intracellular receptor 1	Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane.
VRK1	Serine/threonine-protein kinase VRK1	Serine/threonine kinase involved in the regulation of key cellular processes including the cell cycle, nuclear condensation, transcription regulation, and DNA damage response.
ERLIN1	Erlin-1	Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs).
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
TRPM7	Transient receptor potential cation channel subfamily M member 7	Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain.
PLEKHG5	Pleckstrin homology domain-containing family G member 5	Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.22

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	6.2×	0.158
Scaffold/PPI	1	1.9×	0.687
Other/Unknown	5	1.0×	0.687
Transcription factor	1	0.9×	0.687

Per-gene assignment

Symbol	Family	Druggable?	InterPro (top 3)
SPG11	Other/Unknown	no	Spatacsin, Spatacsin_C_dom
FUS	Transcription factor	no	RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf
ALS2	Other/Unknown	no	DH_dom, Reg_chr_condens, VPS9
SIGMAR1	Other/Unknown	no	ERG2_sigma1_rcpt-like
VRK1	Kinase	yes	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ERLIN1	Other/Unknown	no	Band_7, Erlin1/2, Band_7/SPFH_dom_sf
SYNE1	Other/Unknown	no	Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
TRPM7	Kinase	yes	a-kinase_dom, Kinase-like_dom_sf, TRPM7_a-kinase_dom
PLEKHG5	Scaffold/PPI	no	DH_dom, PH_domain, PH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

8 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
right hemisphere of cerebellum	3
cerebellar hemisphere	3
oocyte	2
secondary oocyte	2
bronchial epithelial cell	1
granulocyte	1
right testis	1
ventricular zone	1
cerebellar cortex	1
cerebellum	1
liver	1
right lobe of liver	1
stromal cell of endometrium	1
bone marrow	1
esophagus squamous epithelium	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPG11	295	ubiquitous	marker	bronchial epithelial cell, granulocyte, calcaneal tendon
FUS	304	ubiquitous	marker	right testis, ventricular zone, right hemisphere of cerebellum
ALS2	254	ubiquitous	marker	cerebellum, cerebellar cortex, cerebellar hemisphere
SIGMAR1	282	ubiquitous	marker	right lobe of liver, stromal cell of endometrium, liver
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte
ERLIN1	289	ubiquitous	marker	secondary oocyte, oocyte, esophagus squamous epithelium
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
TRPM7	247	ubiquitous	marker	left ventricle myocardium, calcaneal tendon, cardiac muscle of right atrium
PLEKHG5	175	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FUS	5,250
VRK1	3,022
SYNE1	2,886
ALS2	2,652
TRPM7	1,995
SIGMAR1	1,993
SPG11	1,691
ERLIN1	1,560
PLEKHG5	966

Intra-cohort edges

A	B	Sources
ALS2	FUS	string_interaction
ALS2	SPG11	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VRK1	Q99986	26
FUS	P35637	23
SIGMAR1	Q99720	5
SPG11	Q96JI7	3
ERLIN1	O75477	3
SYNE1	Q8NF91	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALS2	Q96Q42	74.69
TRPM7	Q96QT4	69.90
PLEKHG5	O94827	64.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Initiation of Nuclear Envelope (NE) Reformation	1	75.1×	0.128	VRK1
Nuclear Envelope Breakdown	1	57.1×	0.128	VRK1
TRP channels	1	51.0×	0.128	TRPM7
Rab regulation of trafficking	1	46.0×	0.128	ALS2
Meiosis	1	35.7×	0.128	SYNE1
RND1 GTPase cycle	1	33.2×	0.128	PLEKHG5
RND3 GTPase cycle	1	32.4×	0.128	PLEKHG5
Defective CFTR causes cystic fibrosis	1	27.4×	0.128	ERLIN1
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	24.2×	0.128	ERLIN1
Reproduction	1	23.8×	0.128	SYNE1
NRAGE signals death through JNK	1	23.0×	0.128	PLEKHG5
Meiotic synapsis	1	17.6×	0.140	SYNE1
G alpha (12/13) signalling events	1	17.2×	0.140	PLEKHG5
RAB GEFs exchange GTP for GDP on RABs	1	15.5×	0.140	ALS2
ABC-family protein mediated transport	1	15.2×	0.140	ERLIN1
Potential therapeutics for SARS	1	14.3×	0.140	SIGMAR1
mRNA Polyadenylation	1	11.0×	0.170	FUS
Processing of Capped Intron-Containing Pre-mRNA	1	10.3×	0.171	FUS
RHOA GTPase cycle	1	9.3×	0.178	PLEKHG5
RAC1 GTPase cycle	1	7.6×	0.197	ALS2
RHO GTPase cycle	1	7.5×	0.197	ALS2
SARS-CoV Infections	1	6.9×	0.197	SIGMAR1
mRNA Splicing - Major Pathway	1	6.8×	0.197	FUS
Dengue Virus-Host Interactions	1	5.7×	0.223	FUS
Membrane Trafficking	1	4.6×	0.245	ALS2
Cell Cycle	1	4.5×	0.245	SYNE1
Vesicle-mediated transport	1	4.3×	0.245	ALS2
Signaling by Rho GTPases	1	4.3×	0.245	ALS2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	4.2×	0.245	ALS2
Viral Infection Pathways	1	3.9×	0.255	SIGMAR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neuromuscular junction development	2	117.0×	0.011	SPG11, ALS2
phagosome-lysosome fusion involved in apoptotic cell clearance	1	1872.4×	0.021	SPG11
calcium-dependent cell-matrix adhesion	1	936.2×	0.021	TRPM7
localization within membrane	1	624.1×	0.021	SPG11
nuclear matrix anchoring at nuclear membrane	1	624.1×	0.021	SYNE1
positive regulation of protein localization to chromatin	1	624.1×	0.021	VRK1
axo-dendritic transport	1	468.1×	0.021	SPG11
Cajal body organization	1	468.1×	0.021	VRK1
autophagosome organization	1	374.5×	0.021	SPG11
intracellular magnesium ion homeostasis	1	312.1×	0.021	TRPM7
Golgi disassembly	1	312.1×	0.021	VRK1
walking behavior	1	312.1×	0.021	SPG11
protein autophosphorylation	2	32.3×	0.021	VRK1, TRPM7
protein homooligomerization	2	27.1×	0.021	FUS, ALS2
corticospinal tract morphogenesis	1	267.5×	0.021	SPG11
negative regulation of cholesterol biosynthetic process	1	267.5×	0.021	ERLIN1
mitotic nuclear membrane disassembly	1	208.1×	0.022	VRK1
magnesium ion homeostasis	1	208.1×	0.022	TRPM7
SREBP signaling pathway	1	208.1×	0.022	ERLIN1
endothelial cell chemotaxis	1	187.2×	0.022	PLEKHG5
zinc ion transport	1	170.2×	0.022	TRPM7
regulation of cholesterol biosynthetic process	1	170.2×	0.022	ERLIN1
regulation of endosome size	1	170.2×	0.022	ALS2
response to alcohol	1	170.2×	0.022	SIGMAR1
receptor recycling	1	144.0×	0.025	ALS2
magnesium ion transport	1	133.8×	0.025	TRPM7
motor neuron apoptotic process	1	124.8×	0.025	SPG11
membraneless organelle assembly	1	124.8×	0.025	FUS
necroptotic process	1	117.0×	0.025	TRPM7
regulation of store-operated calcium entry	1	117.0×	0.025	SPG11

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 8

Druggability breadth: 6 of 9 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
SIGMAR1	PENTAZOCINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SIGMAR1	148	4
SPG11	0	0
FUS	0	0
ALS2	0	0
VRK1	0	0
ERLIN1	0	0
SYNE1	0	0
TRPM7	0	0
PLEKHG5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PENTAZOCINE	4	SIGMAR1
PROGESTERONE	4	SIGMAR1
METHYSERGIDE	4	SIGMAR1
DICYCLOMINE	4	SIGMAR1
PROPARACAINE	4	SIGMAR1
PRAMOXINE	4	SIGMAR1
DIMENHYDRINATE	4	SIGMAR1
DIHYDROERGOTAMINE MESYLATE	4	SIGMAR1
CINACALCET HYDROCHLORIDE	4	SIGMAR1
AZELASTINE HYDROCHLORIDE	4	SIGMAR1
METHAMPHETAMINE	4	SIGMAR1
BENZTROPINE	4	SIGMAR1
LEVOBUNOLOL	4	SIGMAR1
DEXCHLORPHENIRAMINE	4	SIGMAR1
RAMELTEON	4	SIGMAR1
OXYBUTYNIN	4	SIGMAR1
MIFEPRISTONE	4	SIGMAR1
ILOPERIDONE	4	SIGMAR1
TRIHEXYPHENIDYL	4	SIGMAR1
TRIFLUPERIDOL	4	SIGMAR1
TEGASEROD MALEATE	4	SIGMAR1
HYDROXYCHLOROQUINE	4	SIGMAR1
PRAZOSIN HYDROCHLORIDE	4	SIGMAR1
VILAZODONE HYDROCHLORIDE	4	SIGMAR1
CLEMASTINE	4	SIGMAR1
DOXEPIN	4	SIGMAR1
PROPRANOLOL HYDROCHLORIDE	4	SIGMAR1
BETAXOLOL HYDROCHLORIDE	4	SIGMAR1
LOPERAMIDE HYDROCHLORIDE	4	SIGMAR1
TERCONAZOLE	4	SIGMAR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SIGMAR1	619	Binding:610, Functional:5, ADMET:3, Unclassified:1
VRK1	74	Binding:74
TRPM7	34	Binding:34
FUS	7	Binding:7
SPG11	1	Binding:1
ERLIN1	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SIGMAR1	619

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; 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)
PENTAZOCINE	4	SIGMAR1
PROGESTERONE	4	SIGMAR1
METHYSERGIDE	4	SIGMAR1
DICYCLOMINE	4	SIGMAR1
PROPARACAINE	4	SIGMAR1
PRAMOXINE	4	SIGMAR1
DIMENHYDRINATE	4	SIGMAR1
DIHYDROERGOTAMINE MESYLATE	4	SIGMAR1
CINACALCET HYDROCHLORIDE	4	SIGMAR1
AZELASTINE HYDROCHLORIDE	4	SIGMAR1
METHAMPHETAMINE	4	SIGMAR1
BENZTROPINE	4	SIGMAR1
LEVOBUNOLOL	4	SIGMAR1
DEXCHLORPHENIRAMINE	4	SIGMAR1
RAMELTEON	4	SIGMAR1
OXYBUTYNIN	4	SIGMAR1
MIFEPRISTONE	4	SIGMAR1
ILOPERIDONE	4	SIGMAR1
TRIHEXYPHENIDYL	4	SIGMAR1
TRIFLUPERIDOL	4	SIGMAR1
TEGASEROD MALEATE	4	SIGMAR1
HYDROXYCHLOROQUINE	4	SIGMAR1
PRAZOSIN HYDROCHLORIDE	4	SIGMAR1
VILAZODONE HYDROCHLORIDE	4	SIGMAR1
CLEMASTINE	4	SIGMAR1
DOXEPIN	4	SIGMAR1
PROPRANOLOL HYDROCHLORIDE	4	SIGMAR1
BETAXOLOL HYDROCHLORIDE	4	SIGMAR1
LOPERAMIDE HYDROCHLORIDE	4	SIGMAR1
TERCONAZOLE	4	SIGMAR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SIGMAR1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	VRK1
D	Druggable family + AlphaFold only, no drug	1	TRPM7
E	Difficult family or no structure, no drug	6	SPG11, FUS, ALS2, ERLIN1, SYNE1, PLEKHG5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPG11	1	—
FUS	7	—
ALS2	0	—
VRK1	74	—
ERLIN1	1	—
SYNE1	0	—
TRPM7	34	—
PLEKHG5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: SPG11, FUS, ALS2, SIGMAR1, VRK1, ERLIN1, SYNE1, TRPM7, PLEKHG5