Spinal muscular atrophy

disease

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Summary

Spinal muscular atrophy (MONDO:0001516) is a disease (an umbrella term covering 19 Mondo subtypes) caused by SMN1 (GenCC Definitive), with 10 cohort genes and 193 clinical trials. Top therapeutic interventions include nusinersen, risdiplam, and phenylbutanoic acid.

At a glance

Causal gene: SMN1 (GenCC Definitive)
Umbrella term: 19 Mondo subtypes
Cohort genes: 10
ClinVar variants: 55
Clinical trials: 193

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spinal muscular atrophy
Mondo ID	MONDO:0001516
EFO	EFO:0008525
MeSH	D009134
OMIM	253300
DOID	DOID:12377
ICD-11	71074342
NCIT	C85075
SNOMED CT	5262007
UMLS	C0026847
MedGen	7755
GARD	0007674
Is cancer (heuristic)	no

Data availability: 55 ClinVar variants · 2 GenCC gene-disease records · 16 cell lines.

Disease family

An umbrella term covering 19 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 › spinal muscular atrophy

Related subtypes (2): amyotrophic lateral sclerosis, poliomyelitis

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

55 retrieved; paginated sample, class counts are floors:

16 pathogenic, 9 conflicting classifications of pathogenicity, 9 uncertain significance, 7 likely pathogenic, 5 likely benign, 5 pathogenic/likely pathogenic, 2 benign, 1 not provided, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3246280	NC_000005.9:g.(?70247773)(70247773_?)del		Pathogenic	criteria provided, single submitter
55857	NM_001003800.2(BICD2):c.320C>T (p.Ser107Leu)	BICD2	Pathogenic	criteria provided, multiple submitters, no conflicts
162033	NM_001376.5(DYNC1H1):c.791G>T (p.Arg264Leu)	DYNC1H1	Pathogenic	criteria provided, multiple submitters, no conflicts
637263	NM_002180.3(IGHMBP2):c.388C>T (p.Arg130Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699219	NM_000344.4(SMN1):c.549del (p.Lys184fs)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1699436	NM_000344.4(SMN1):c.291del (p.Lys97fs)	SMN1	Pathogenic	criteria provided, single submitter
1929368	NM_000344.4(SMN1):c.835G>C (p.Gly279Arg)	SMN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338271	NC_000005.10:g.(?70951941)(70951991_?)del	SMN1	Pathogenic	no assertion criteria provided
457356	NC_000005.10:g.(?70951921)(70952011_?)del	SMN1	Pathogenic	criteria provided, single submitter
571461	NM_000344.4(SMN1):c.835-21_*3+17del	SMN1	Pathogenic	criteria provided, single submitter
583423	NC_000005.10:g.(?70951941)(70951991_?)del	SMN1	Pathogenic	criteria provided, single submitter
632985	NM_000344.4(SMN1):c.835-2A>G	SMN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632989	NM_000344.4(SMN1):c.835-1G>A	SMN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
651822	NC_000005.10:g.(?70951931)(70952001_?)del	SMN1	Pathogenic	criteria provided, single submitter
832287	NC_000005.10:g.(?70951912)(70951994_?)del	SMN1	Pathogenic	criteria provided, single submitter
916136	GRCh37/hg19 5q13.2(chr5:70247768-70247821)	SMN1	Pathogenic	no assertion criteria provided
9166	NM_000344.4(SMN1):c.815A>G (p.Tyr272Cys)	SMN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9168	NM_000344.4(SMN1):c.5C>G (p.Ala2Gly)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
9176	NM_000344.4(SMN1):c.283G>C (p.Gly95Arg)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
928626	NM_000344.4(SMN1):c.*3+1G>C	SMN1	Pathogenic	criteria provided, single submitter
873318	NM_003384.3(VRK1):c.1135_1136del (p.Gln379fs)	VRK1	Pathogenic	criteria provided, single submitter
986345	NM_002180.3(IGHMBP2):c.34_35insCC (p.Lys12fs)	IGHMBP2	Likely pathogenic	criteria provided, single submitter
2203655	NM_000344.4(SMN1):c.835-18_835-12del	SMN1	Likely pathogenic	criteria provided, single submitter
2581366	NM_000344.4(SMN1):c.3+4_3+7del	SMN1	Likely pathogenic	criteria provided, single submitter
3239631	NM_000344.4(SMN1):c.347T>C (p.Ile116Thr)	SMN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
495832	NM_000344.4(SMN1):c.855dup (p.Glu286fs)	SMN1	Likely pathogenic	criteria provided, single submitter
632984	NM_000344.4(SMN1):c.835-2A>T	SMN1	Likely pathogenic	criteria provided, single submitter
634946	NM_000344.4(SMN1):c.*3+1G>A	SMN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1256472	NM_000344.4(SMN1):c.855_858del (p.Arg288fs)	SMN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2190592	NM_000344.4(SMN1):c.861_864del (p.Arg288fs)	SMN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
SMN1	Definitive	Autosomal recessive	spinal muscular atrophy, type 1	12
RBM7	Moderate	Autosomal recessive	spinal muscular atrophy

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMN1	Orphanet:83330	Proximal spinal muscular atrophy type 1
SMN1	Orphanet:83418	Proximal spinal muscular atrophy type 2
SMN1	Orphanet:83419	Proximal spinal muscular atrophy type 3
SMN1	Orphanet:83420	Proximal spinal muscular atrophy type 4
SCO2	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
SCO2	Orphanet:521411	Autosomal recessive axonal Charcot-Marie-Tooth disease due to copper metabolism defect
SCO2	Orphanet:98619	Rare isolated myopia
SMN2	Orphanet:83330	Proximal spinal muscular atrophy type 1
SMN2	Orphanet:83418	Proximal spinal muscular atrophy type 2
SMN2	Orphanet:83419	Proximal spinal muscular atrophy type 3
SMN2	Orphanet:83420	Proximal spinal muscular atrophy type 4
VRK1	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:423894	Microcephaly-complex motor and sensory axonal neuropathy syndrome
ARHGEF10	Orphanet:140481	Autosomal dominant slowed nerve conduction velocity
BICD2	Orphanet:363454	BICD2-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress type 1

Cohort genes → proteins

10 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMN1	HGNC:11117	ENSG00000172062	Q16637	Survival motor neuron protein	gencc,clinvar
RBM7	HGNC:9904	ENSG00000076053	Q9Y580	RNA-binding protein 7	gencc
SCO2	HGNC:10604	ENSG00000284194	O43819	Cytochrome c oxidase assembly factor SCO2	clinvar
SMN2	HGNC:11118	ENSG00000205571	Q16637	Survival motor neuron protein	clinvar
TLL2	HGNC:11844	ENSG00000095587	Q9Y6L7	Tolloid-like protein 2	clinvar
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	clinvar
ARHGEF10	HGNC:14103	ENSG00000104728	O15013	Rho guanine nucleotide exchange factor 10	clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMN1	Survival motor neuron protein	The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs.
RBM7	RNA-binding protein 7	RNA-binding subunit of the trimeric nuclear exosome targeting (NEXT) complex, a complex that functions as an RNA exosome cofactor that directs a subset of non-coding short-lived RNAs for exosomal degradation.
SCO2	Cytochrome c oxidase assembly factor SCO2	Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2); together with SCO1, facilitates the incorporation of copper into the Cu(A) site of MT-CO2/COX2.
SMN2	Survival motor neuron protein	The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs.
TLL2	Tolloid-like protein 2	Protease which specifically processes pro-lysyl oxidase.
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.
ARHGEF10	Rho guanine nucleotide exchange factor 10	May play a role in developmental myelination of peripheral nerves.
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 6 · Druggable fraction: 0.2

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
Protease	1	3.7×	0.657
Kinase	1	2.8×	0.657
Scaffold/PPI	1	1.7×	0.657
Other/Unknown	6	1.1×	0.657
Transcription factor	1	0.8×	0.725

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMN1	Other/Unknown	no		Tudor, SMN_Tudor, Smn1
RBM7	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBM7_RRM
SCO2	Other/Unknown	no		SCO1/SenC, Thioredoxin_domain, Synth_of_cyt-c-oxidase_Sco1/2
SMN2	Other/Unknown	no		Tudor, SMN_Tudor, Smn1
TLL2	Protease	yes		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom
VRK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ARHGEF10	Scaffold/PPI	no		DH_dom, WD40/YVTN_repeat-like_dom_sf, DBL_dom_sf
BICD2	Other/Unknown	no		BICD
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase

Expression context

Cohort genes with no expression data: 0.

7 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
ventricular zone	2
endocervix	1
calcaneal tendon	1
cartilage tissue	1
mucosa of sigmoid colon	1
granulocyte	1
mucosa of transverse colon	1
right uterine tube	1
colonic epithelium	1
endometrium	1
smooth muscle tissue	1
apex of heart	1
buccal mucosa cell	1
primordial germ cell in gonad	1
bone marrow	1
oocyte	1
secondary oocyte	1
right lung	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMN1	134		marker	ventricular zone, ganglionic eminence, endocervix
RBM7	278	ubiquitous	marker	cartilage tissue, mucosa of sigmoid colon, calcaneal tendon
SCO2	260	ubiquitous	yes	right uterine tube, granulocyte, mucosa of transverse colon
SMN2	134		marker	colonic epithelium, endometrium, smooth muscle tissue
TLL2	149	broad	marker	buccal mucosa cell, primordial germ cell in gonad, apex of heart
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte
ARHGEF10	134	ubiquitous	yes	sural nerve, tibial nerve, right lung
BICD2	290	ubiquitous	marker	gingival epithelium, gingiva, hair follicle
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC1H1	4,215
SMN1	3,595
SMN2	3,595
VRK1	3,022
BICD2	2,275
SCO2	2,043
RBM7	1,281
IGHMBP2	1,265
ARHGEF10	1,071
TLL2	485

Intra-cohort edges

A	B	Sources
BICD2	DYNC1H1	string_interaction
DYNC1H1	IGHMBP2	string_interaction
IGHMBP2	SMN2	string_interaction
SMN1	SMN2	biogrid_interaction, intact
SMN2	VRK1	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
VRK1	Q99986	26
SMN1	Q16637	15
SMN2	Q16637	15
RBM7	Q9Y580	6
IGHMBP2	P38935	4
BICD2	Q8TD16	2
SCO2	O43819	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TLL2	Q9Y6L7	81.98
ARHGEF10	O15013	65.56

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. Enrichment computed across 10 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of non-coding RNA	2	141.0×	0.006	SMN1, SMN2
SARS-CoV-2 modulates host translation machinery	2	49.8×	0.014	SMN1, SMN2
snRNP Assembly	2	47.0×	0.014	SMN1, SMN2
COPI-independent Golgi-to-ER retrograde traffic	2	46.1×	0.014	BICD2, DYNC1H1
SARS-CoV-2-host interactions	2	26.4×	0.033	SMN1, SMN2
SARS-CoV-2 Infection	2	17.9×	0.059	SMN1, SMN2
Anchoring fibril formation	1	84.6×	0.100	TLL2
SARS-CoV Infections	2	12.3×	0.100	SMN1, SMN2
Initiation of Nuclear Envelope (NE) Reformation	1	66.8×	0.106	VRK1
Crosslinking of collagen fibrils	1	63.4×	0.106	TLL2
Nuclear Envelope Breakdown	1	50.8×	0.111	VRK1
Metabolism of RNA	2	9.3×	0.111	SMN1, SMN2
Nuclear RNA decay	1	34.3×	0.137	RBM7
Aggrephagy	1	27.6×	0.137	DYNC1H1
Complex IV assembly	1	25.4×	0.137	SCO2
Cell death signalling via NRAGE, NRIF and NADE	1	24.4×	0.137	ARHGEF10
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	21.5×	0.137	DYNC1H1
p75 NTR receptor-mediated signalling	1	20.8×	0.137	ARHGEF10
NRAGE signals death through JNK	1	20.5×	0.137	ARHGEF10
Collagen biosynthesis and modifying enzymes	1	18.9×	0.137	TLL2
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	1	18.1×	0.137	RBM7
Loss of Nlp from mitotic centrosomes	1	17.6×	0.137	DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	1	17.6×	0.137	DYNC1H1
RHOB GTPase cycle	1	17.1×	0.137	ARHGEF10
AURKA Activation by TPX2	1	16.9×	0.137	DYNC1H1
RHOC GTPase cycle	1	16.3×	0.137	ARHGEF10
Death Receptor Signaling	1	15.5×	0.137	ARHGEF10
G alpha (12/13) signalling events	1	15.3×	0.137	ARHGEF10
Recruitment of mitotic centrosome proteins and complexes	1	15.1×	0.137	DYNC1H1
Golgi-to-ER retrograde transport	1	14.8×	0.137	BICD2

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA-templated transcription termination	2	340.4×	8e-04	SMN1, SMN2
spliceosomal complex assembly	2	133.8×	0.002	SMN1, SMN2
spliceosomal snRNP assembly	2	129.1×	0.002	SMN1, SMN2
negative regulation of skeletal muscle tissue growth	1	936.2×	0.013	TLL2
microtubule anchoring at microtubule organizing center	1	936.2×	0.013	BICD2
snRNA catabolic process	1	624.1×	0.013	RBM7
positive regulation of protein localization to chromatin	1	624.1×	0.013	VRK1
muscle system process	1	468.1×	0.013	SCO2
Cajal body organization	1	468.1×	0.013	VRK1
minus-end-directed organelle transport along microtubule	1	468.1×	0.013	BICD2
regulation of metaphase plate congression	1	374.5×	0.014	DYNC1H1
establishment of spindle localization	1	312.1×	0.015	DYNC1H1
Golgi disassembly	1	312.1×	0.015	VRK1
positive regulation of spindle assembly	1	234.1×	0.018	DYNC1H1
mitotic nuclear membrane disassembly	1	208.1×	0.019	VRK1
positive regulation of intracellular transport	1	187.2×	0.020	DYNC1H1
retrograde axonal transport	1	170.2×	0.020	DYNC1H1
P-body assembly	1	117.0×	0.026	DYNC1H1
intracellular copper ion homeostasis	1	104.0×	0.026	SCO2
centrosome duplication	1	104.0×	0.026	ARHGEF10
myelination in peripheral nervous system	1	98.5×	0.026	ARHGEF10
centrosome localization	1	98.5×	0.026	BICD2
respiratory electron transport chain	1	93.6×	0.026	SCO2
regulation of mitotic spindle organization	1	93.6×	0.026	DYNC1H1
protein localization to Golgi apparatus	1	89.2×	0.026	BICD2
nuclear migration	1	81.4×	0.028	DYNC1H1
mitochondrial respiratory chain complex IV assembly	1	69.3×	0.028	SCO2
regulation of neuron migration	1	69.3×	0.028	VRK1
stress granule assembly	1	66.9×	0.028	DYNC1H1
positive regulation of Rho protein signal transduction	1	64.6×	0.028	ARHGEF10

Therapeutics

Drugs indicated for this disease

2 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Onasemnogene Abeparvovec	Approved (phase 4)
Risdiplam	Approved (phase 4)
Apitegromab	Phase 3 (in late-stage trials)
Levocarnitine	Phase 3 (in late-stage trials)
Nusinersen	Phase 3 (in late-stage trials)
Taldefgrobep Alfa	Phase 3 (in late-stage trials)
Valproic Acid	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Celecoxib, Dalfampridine, Hydroxyurea, Olesoxime, Pyridostigmine, Reldesemtiv, Riluzole, Somatropin.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 7

Druggability breadth: 6 of 10 evidence-associated genes (60%) 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
SMN1	BEPRIDIL
SMN2	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMN1	352	4
SMN2	352	4
DYNC1H1	1	2
RBM7	0	0
SCO2	0	0
TLL2	0	0
VRK1	0	0
ARHGEF10	0	0
BICD2	0	0
IGHMBP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SMN1, SMN2
PHENYLBUTAZONE	4	SMN1, SMN2
PROGESTERONE	4	SMN1, SMN2
CLOTRIMAZOLE	4	SMN1, SMN2
CHOLECALCIFEROL	4	SMN1, SMN2
NABUMETONE	4	SMN1, SMN2
GLIPIZIDE	4	SMN1, SMN2
SALMETEROL XINAFOATE	4	SMN1, SMN2
AMIODARONE HYDROCHLORIDE	4	SMN1, SMN2
DIBUCAINE	4	SMN1, SMN2
PHENELZINE	4	SMN1, SMN2
FELBAMATE	4	SMN1, SMN2
FURAZOLIDONE	4	SMN1, SMN2
CHLORMADINONE ACETATE	4	SMN1, SMN2
AMOXAPINE	4	SMN1, SMN2
IDARUBICIN	4	SMN1, SMN2
EDROPHONIUM CHLORIDE	4	SMN1, SMN2
TRIFLURIDINE	4	SMN1, SMN2
ACITRETIN	4	SMN1, SMN2
DECAMETHONIUM BROMIDE	4	SMN1, SMN2
CLOBETASOL PROPIONATE	4	SMN1, SMN2
LABETALOL HYDROCHLORIDE	4	SMN1, SMN2
PROTRIPTYLINE HYDROCHLORIDE	4	SMN1, SMN2
MORICIZINE HYDROCHLORIDE	4	SMN1, SMN2
SULCONAZOLE NITRATE	4	SMN1, SMN2
PARGYLINE HYDROCHLORIDE	4	SMN1, SMN2
ESTRADIOL ACETATE	4	SMN1, SMN2
TRIPELENNAMINE HYDROCHLORIDE	4	SMN1, SMN2
PROMAZINE HYDROCHLORIDE	4	SMN1, SMN2
PYRITHIONE ZINC	4	SMN1, SMN2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VRK1	74	Binding:74
SMN1	29	Binding:23, Functional:6
SMN2	29	Binding:23, Functional:6
DYNC1H1	7	Binding:7
TLL2	5	Binding:5
SCO2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IGHMBP2	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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)
BEPRIDIL	4	SMN1, SMN2
PHENYLBUTAZONE	4	SMN1, SMN2
PROGESTERONE	4	SMN1, SMN2
CLOTRIMAZOLE	4	SMN1, SMN2
CHOLECALCIFEROL	4	SMN1, SMN2
NABUMETONE	4	SMN1, SMN2
GLIPIZIDE	4	SMN1, SMN2
SALMETEROL XINAFOATE	4	SMN1, SMN2
AMIODARONE HYDROCHLORIDE	4	SMN1, SMN2
DIBUCAINE	4	SMN1, SMN2
PHENELZINE	4	SMN1, SMN2
FELBAMATE	4	SMN1, SMN2
FURAZOLIDONE	4	SMN1, SMN2
CHLORMADINONE ACETATE	4	SMN1, SMN2
AMOXAPINE	4	SMN1, SMN2
IDARUBICIN	4	SMN1, SMN2
EDROPHONIUM CHLORIDE	4	SMN1, SMN2
TRIFLURIDINE	4	SMN1, SMN2
ACITRETIN	4	SMN1, SMN2
DECAMETHONIUM BROMIDE	4	SMN1, SMN2
CLOBETASOL PROPIONATE	4	SMN1, SMN2
LABETALOL HYDROCHLORIDE	4	SMN1, SMN2
PROTRIPTYLINE HYDROCHLORIDE	4	SMN1, SMN2
MORICIZINE HYDROCHLORIDE	4	SMN1, SMN2
SULCONAZOLE NITRATE	4	SMN1, SMN2
PARGYLINE HYDROCHLORIDE	4	SMN1, SMN2
ESTRADIOL ACETATE	4	SMN1, SMN2
TRIPELENNAMINE HYDROCHLORIDE	4	SMN1, SMN2
PROMAZINE HYDROCHLORIDE	4	SMN1, SMN2
PYRITHIONE ZINC	4	SMN1, SMN2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SMN1, SMN2
B	Phased (≥1) drug, not yet approved	1	DYNC1H1
C	Druggable family + PDB, no drug	1	VRK1
D	Druggable family + AlphaFold only, no drug	1	TLL2
E	Difficult family or no structure, no drug	5	RBM7, SCO2, ARHGEF10, BICD2, IGHMBP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IGHMBP2	0	SMN2
RBM7	0	—
SCO2	1	—
TLL2	5	—
VRK1	74	—
ARHGEF10	0	—
BICD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 193.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	134
PHASE3	16
PHASE2	16
PHASE1/PHASE2	11
PHASE1	7
PHASE4	4
PHASE2/PHASE3	3
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05232929	PHASE4	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Risdiplam in Participants With Spinal Muscular Atrophy (SMA)
NCT05522361	PHASE4	ACTIVE_NOT_RECRUITING	Risdiplam in Patients With Spinal Muscular Atrophy Previously Treated With Nusinersen
NCT07448610	PHASE4	NOT_YET_RECRUITING	ASsessing The REAl-world Safety & Effectiveness of Spinal Muscular Atrophy Participants Treated With Intrathecal Onasemnogene Abeparvovec-brve (OAV101B) (ITVISMA®): A U.S. Pragmatic Multicenter Study (STREAM)
NCT01422200	PHASE4	COMPLETED	Flu Vaccine Study in Neuromuscular Patients 2011
NCT04042025	PHASE3	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi
NCT05067790	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn About the Effect of Higher Doses of Nusinersen (BIIB058) Given as Injections to Participants With Spinal Muscular Atrophy (SMA) Who Were Previously Treated With Risdiplam (ASCEND)
NCT05115110	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study to Investigate the Safety and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Participants With Spinal Muscular Atrophy
NCT05335876	PHASE3	RECRUITING	Long-term Follow-up of Patients With Spinal Muscular Atrophy Treated With OAV101 in Clinical Trials
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT07265232	PHASE3	RECRUITING	Real World Clinical Effectiveness & Safety of Vesemnogene Lantuparvovec for Spinal Muscular Atrophy (SMA) in Low-middle Income Countries (LMIC).
NCT07444476	PHASE3	RECRUITING	A Study to Learn About Salanersen’s (BIIB115) Effects on Movement and Its Safety in Participants Aged 15 to 60 Years With Spinal Muscular Atrophy (SMA) Who Are Either New to SMA Treatment or Were Previously Treated With Risdiplam
NCT00485511	PHASE2/PHASE3	COMPLETED	A Trial of Hydroxyurea in Spinal Muscular Atrophy
NCT01645787	PHASE2/PHASE3	COMPLETED	Short and Long Term Treatment With 4-AP in Ambulatory SMA Patients
NCT01671384	PHASE3	UNKNOWN	Valproate and Levocarnitine in Children With Spinal Muscular Atrophy
NCT02193074	PHASE3	TERMINATED	A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
NCT02292537	PHASE3	COMPLETED	A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)
NCT02594124	PHASE3	COMPLETED	A Study for Participants With Spinal Muscular Atrophy (SMA) Who Previously Participated in Nusinersen (ISIS 396443) Investigational Studies
NCT03505099	PHASE3	COMPLETED	Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2
NCT03837184	PHASE3	COMPLETED	Single-Dose Gene Replacement Therapy Using for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies
NCT04851873	PHASE3	COMPLETED	Safety and Efficacy of Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA)
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05386680	PHASE3	COMPLETED	Phase IIIb, Open-label, Multi-center Study to Evaluate Safety, Tolerability and Efficacy of OAV101 Administered Intrathecally to Participants With SMA Who Discontinued Treatment With Nusinersen or Risdiplam
NCT05614531	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Clinical Trial to Assess the Safety and Efficacy of EXG001-307 in Patients with Spinal Muscular Atrophy Type 1
NCT05747261	PHASE1/PHASE2	RECRUITING	Study of the Safety and Efficacy of an Adeno-Associated Viral Vector Carrying the SMN Gene After a Single Intravenous Administration of Escalating Doses in Children With Spinal Muscular Atrophy (BLUEBELL)
NCT05794139	PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of NMD670 in Ambulatory Adult Patients With Type 3 Spinal Muscular Atrophy
NCT05824169	PHASE1/PHASE2	RECRUITING	Evaluation of Safety and Efficacy of Gene Therapy Drug in the Treatment of Spinal Muscular Atrophy (SMA) Type 1 Patients
NCT06288230	PHASE1/PHASE2	RECRUITING	An Open Label Study of Gene Therapy Product (Vesemnogene Lantuparvovec) in Spinal Muscular Atrophy
NCT07047144	PHASE2	RECRUITING	A Study to Evaluate How Apitegromab Works in Subjects Who Are Less Than 2 Years Old and Have Spinal Muscular Atrophy
NCT07070999	PHASE1/PHASE2	RECRUITING	Study of Safety, Tolerability and Efficacy of GB221 in Infants With Spinal Muscular Atrophy Type 1
NCT07287982	PHASE2	RECRUITING	A Study to Assess the Safety, Tolerability, Efficacy, Pharmacokinetics, and Immunogenicity of Intravenous Administration of ARGX-119 in Pediatric Participants Aged 5 to Less Than 18 Years With Spinal Muscular Atrophy
NCT00004771	PHASE2	COMPLETED	Phase II Study of Leuprolide and Testosterone for Men With Kennedy’s Disease or Other Motor Neuron Disease
NCT00227266	PHASE2	COMPLETED	Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy
NCT00439218	PHASE1/PHASE2	TERMINATED	Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Type I
NCT00439569	PHASE1/PHASE2	TERMINATED	Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Types II or III
NCT00481013	PHASE2	COMPLETED	Valproic Acid in Ambulant Adults With Spinal Muscular Atrophy
NCT00528268	PHASE1/PHASE2	COMPLETED	Study to Evaluate Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy
NCT00661453	PHASE1/PHASE2	COMPLETED	CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I
NCT01028833	PHASE2	COMPLETED	Effects of Power Mobility on Young Children With Severe Motor Impairments
NCT01302600	PHASE2	COMPLETED	Safety and Efficacy of Olesoxime (TRO19622) in 3-25 Years SMA Patients.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NUSINERSEN	4	17
RISDIPLAM	4	9
PHENYLBUTANOIC ACID	4	6
ONASEMNOGENE ABEPARVOVEC	4	4
VALPROIC ACID	4	4
LEVOCARNITINE	4	3
DALFAMPRIDINE	4	1
HYDROXYUREA	4	1
LEUPROLIDE	4	1
PYRIDOSTIGMINE	4	1
TESTOSTERONE	4	1
APITEGROMAB	3	4
CARNITINE	3	3
GLUCAGON-LIKE PEPTIDE II	3	1
OLESOXIME	3	1
RELDESEMTIV	3	1
TALDEFGROBEP ALFA	3	1
BRANAPLAM	2	1
EMUGROBART	2	1
SALANERSEN	2	1
DEXTROCARNITINE	0	3
CHEMBL4073387	0	1
CHEMBL4746472	0	1

Cohort genes: SMN1, RBM7, SCO2, SMN2, TLL2, VRK1, ARHGEF10, BICD2, DYNC1H1, IGHMBP2
Drugs: Nusinersen, Risdiplam, Phenylbutanoic Acid, Onasemnogene Abeparvovec, Valproic Acid, Levocarnitine, Dalfampridine, Hydroxyurea, Leuprolide, Pyridostigmine, Testosterone, Apitegromab, Glucagon-Like Peptide Ii, Olesoxime, Reldesemtiv, Taldefgrobep Alfa