spinal muscular atrophy, type II

Summary

spinal muscular atrophy, type II (MONDO:0009673) is a disease caused by SMN1 (GenCC Strong), with 1 cohort gene and 18 clinical trials. Top therapeutic interventions include phenylbutanoic acid, acetaminophen, and nusinersen.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: SMN1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21
• Clinical trials: 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.0322	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	2	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spinal muscular atrophy, type II
Mondo ID	MONDO:0009673
MeSH	C536879
OMIM	253550
Orphanet	83418
DOID	DOID:0050530
ICD-11	867148636
SNOMED CT	128212001
UMLS	C0393538
MedGen	95975
GARD	0004945
Is cancer (heuristic)	no

Also known as: chronic infantile spinal muscular atrophy · chronic spinal muscular atrophy · Dubowitz disease · Intermediate spinal muscular atrophy · muscular atrophy, spinal, infantile chronic form · muscular atrophy, spinal, intermediate type · SMA II · SMA type 2 · SMA type II · SMA-II · SMA2 · spinal muscular atrophy type 2 · spinal muscular atrophy type II · spinal muscular atrophy, type II · spinal muscular atrophy-2

Data availability: 21 ClinVar variants · 2 GenCC gene-disease records · 37 cell lines.

Disease family

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 › proximal spinal muscular atrophy › spinal muscular atrophy, type II

Related subtypes (5): spinal muscular atrophy, type 1, spinal muscular atrophy, type III, spinal muscular atrophy, type IV, lower motor neuron syndrome with late-adult onset, autosomal dominant childhood-onset proximal spinal muscular atrophy

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

21 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
3239633	NM_000344.4(SMN1):c.603del (p.Pro203fs)	SMN1	Pathogenic	criteria provided, single submitter
3239634	NM_000344.4(SMN1):c.579del (p.Leu194fs)	SMN1	Pathogenic	criteria provided, single submitter
3239713	NM_000344.4(SMN1):c.490C>T (p.Gln164Ter)	SMN1	Pathogenic	criteria provided, single submitter
3239714	NM_000344.4(SMN1):c.850C>T (p.Gln284Ter)	SMN1	Pathogenic	criteria provided, single submitter
3338105	NM_000344.4(SMN1):c.82-2596_723+467del	SMN1	Pathogenic	criteria provided, single submitter
431179	NC_000005.10:g.70946066_70946176del	SMN1	Pathogenic	no assertion criteria provided
632989	NM_000344.4(SMN1):c.835-1G>A	SMN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
634931	NM_000344.4(SMN1):c.48_55dup (p.Val19fs)	SMN1	Pathogenic	criteria provided, single submitter
634947	NM_000344.4(SMN1):c.399_402del (p.Glu134fs)	SMN1	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
9169	NG_008691.1:g.(32498_32055)(33073?)del	SMN1	Pathogenic	no assertion criteria provided
9173	NM_000344.4(SMN1):c.305G>A (p.Trp102Ter)	SMN1	Pathogenic	criteria provided, single submitter
9175	NM_000344.4(SMN1):c.88G>A (p.Asp30Asn)	SMN1	Pathogenic	no assertion criteria provided
9177	NM_000344.4(SMN1):c.332C>G (p.Ala111Gly)	SMN1	Pathogenic	criteria provided, single submitter
3897011	NM_000344.4(SMN1):c.844C>T (p.Gln282Ter)	SMN1	Likely pathogenic	criteria provided, single submitter
1331398	NM_000344.4(SMN1):c.*3+80T>G	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
9164	NM_000344.4(SMN1):c.821C>T (p.Thr274Ile)	SMN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3239715	NM_000344.4(SMN1):c.834+5del	SMN1	Uncertain significance	criteria provided, single submitter
495833	NM_000344.4(SMN1):c.865T>A (p.Cys289Ser)	SMN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
634932	NM_000344.4(SMN1):c.662C>T (p.Pro221Leu)	SMN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 4 · 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

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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMN1	HGNC:11117	ENSG00000172062	Q16637	Survival motor neuron protein	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMN1	Other/Unknown	no		Tudor, SMN_Tudor, Smn1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endocervix	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMN1	134		marker	ventricular zone, ganglionic eminence, endocervix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMN1	3,595

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMN1	Q16637	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	634.4×	0.016	SMN1
SARS-CoV-2 modulates host translation machinery	1	223.9×	0.016	SMN1
snRNP Assembly	1	211.5×	0.016	SMN1
SARS-CoV-2-host interactions	1	119.0×	0.021	SMN1
SARS-CoV-2 Infection	1	80.4×	0.025	SMN1
SARS-CoV Infections	1	55.4×	0.030	SMN1
Metabolism of RNA	1	41.7×	0.034	SMN1
Viral Infection Pathways	1	30.8×	0.041	SMN1
Infectious disease	1	24.8×	0.045	SMN1
Disease	1	13.1×	0.076	SMN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA-templated transcription termination	1	1532.0×	0.002	SMN1
spliceosomal complex assembly	1	601.9×	0.002	SMN1
spliceosomal snRNP assembly	1	581.1×	0.002	SMN1
nervous system development	1	45.9×	0.022	SMN1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMN1	352	4

Drugs targeting cohort genes (top 30)

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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMN1	29	Binding:23, Functional:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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
PHENYLBUTAZONE	4	SMN1
PROGESTERONE	4	SMN1
CLOTRIMAZOLE	4	SMN1
CHOLECALCIFEROL	4	SMN1
NABUMETONE	4	SMN1
GLIPIZIDE	4	SMN1
SALMETEROL XINAFOATE	4	SMN1
AMIODARONE HYDROCHLORIDE	4	SMN1
DIBUCAINE	4	SMN1
PHENELZINE	4	SMN1
FELBAMATE	4	SMN1
FURAZOLIDONE	4	SMN1
CHLORMADINONE ACETATE	4	SMN1
AMOXAPINE	4	SMN1
IDARUBICIN	4	SMN1
EDROPHONIUM CHLORIDE	4	SMN1
TRIFLURIDINE	4	SMN1
ACITRETIN	4	SMN1
DECAMETHONIUM BROMIDE	4	SMN1
CLOBETASOL PROPIONATE	4	SMN1
LABETALOL HYDROCHLORIDE	4	SMN1
PROTRIPTYLINE HYDROCHLORIDE	4	SMN1
MORICIZINE HYDROCHLORIDE	4	SMN1
SULCONAZOLE NITRATE	4	SMN1
PARGYLINE HYDROCHLORIDE	4	SMN1
ESTRADIOL ACETATE	4	SMN1
TRIPELENNAMINE HYDROCHLORIDE	4	SMN1
PROMAZINE HYDROCHLORIDE	4	SMN1
PYRITHIONE ZINC	4	SMN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SMN1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 18.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE3	3
PHASE2	3
PHASE1/PHASE2	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04042025	PHASE3	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05901987	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Evaluation of Safety and Efficacy of Gene Therapy Drug in the Treatment of Spinal Muscular Atrophy (SMA) Type 2 Patients
NCT07047144	PHASE2	RECRUITING	A Study to Evaluate How Apitegromab Works in Subjects Who Are Less Than 2 Years Old and Have Spinal Muscular Atrophy
NCT00439569	PHASE1/PHASE2	TERMINATED	Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Types II or III
NCT01302600	PHASE2	COMPLETED	Safety and Efficacy of Olesoxime (TRO19622) in 3-25 Years SMA Patients.
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT03709784	Not specified	ACTIVE_NOT_RECRUITING	Spinraza in Adult Spinal Muscular Atrophy
NCT06300996	Not specified	ACTIVE_NOT_RECRUITING	Spinal Cord Stimulation for the Treatment of Motor Deficits in People With Spinal Muscular Atrophy - Upper Limb
NCT06772402	Not specified	ENROLLING_BY_INVITATION	GCB-001 in Treatment of Patients With Type II (SMA) Spinal Muscular Atrophy
NCT04813601	Not specified	COMPLETED	Rehabilitative Effect of the Use of a Gait Exoskeleton in Patients With Neuromuscular Disease or Cerebral Palsy
NCT04837157	Not specified	COMPLETED	Evaluation of the Exoskeleton ATLAS 2030 as Robot-assisted Physical Therapy to Children With Neuromuscular Diseases
NCT05416034	Not specified	COMPLETED	Exoskeleton Impact on the Quality of Life on Patients With Spinal Muscular Atrophy
NCT05715749	Not specified	COMPLETED	Body Weight Support Harness System in Spinal Muscular Atrophy
NCT06137612	Not specified	UNKNOWN	Spinal Cord Gray Matter Imaging in Spinal Muscular Atrophy
NCT06632730	Not specified	COMPLETED	Therapeutic Management and Use of Resources and Costs of Spinal Muscular Atrophy in Spain

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHENYLBUTANOIC ACID	4	2
ACETAMINOPHEN	4	1
NUSINERSEN	4	1
RISDIPLAM	4	1
APITEGROMAB	3	4
OLESOXIME	3	1
CHEMBL5592090	0	1