spinal muscular atrophy, type III

Summary

spinal muscular atrophy, type III (MONDO:0009672) is a disease caused by SMN1 (GenCC Strong), with 3 cohort genes and 20 clinical trials. Top therapeutic interventions include pyridostigmine, nusinersen, and risdiplam.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: SMN1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 34
• Clinical trials: 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.61	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.6623	Italy	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spinal muscular atrophy, type III
Mondo ID	MONDO:0009672
OMIM	253400
Orphanet	83419
DOID	DOID:12376
ICD-11	677572815
NCIT	C118847
SNOMED CT	54280009
UMLS	C0152109
MedGen	101816
GARD	0000198
NORD	1342
Is cancer (heuristic)	no

Also known as: childhood spinal muscular atrophy · juvenile spinal muscular atrophy · Kugelberg Welander Syndrome · Kugelberg-Welander disease · Kugelberg-Welander syndrome · KWS · muscular atrophy, juvenile · paediatric spinal muscular atrophy · pediatric spinal muscular atrophy · SMA 3 · SMA type 3 · SMA type III · SMA-III · SMA3 · spinal muscular atrophy III · spinal muscular atrophy of childhood · spinal muscular atrophy type 3 · spinal muscular atrophy, familial · spinal muscular atrophy, mild childhood and adolescent form · spinal muscular atrophy, type III (+2 more)

Data availability: 34 ClinVar variants · 3 GenCC gene-disease records · 17 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 III

Related subtypes (5): spinal muscular atrophy, type 1, spinal muscular atrophy, type II, 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

34 retrieved; paginated sample, class counts are floors:

17 pathogenic, 5 uncertain significance, 4 conflicting classifications of pathogenicity, 4 likely pathogenic, 2 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1679110	NM_000344.3:c.*3+32_*3+33insSVA	SMN1	Pathogenic	criteria provided, single submitter
2443947	NG_008691.1:g.32086_32087ins[N[1090];32074_32086]	SMN1	Pathogenic	no assertion criteria provided
2506919	NM_000344.4(SMN1):c.801G>A (p.Trp267Ter)	SMN1	Pathogenic	criteria provided, single submitter
3239630	NM_000344.4(SMN1):c.13del (p.Ser5fs)	SMN1	Pathogenic	criteria provided, single submitter
39512	NM_000344.4(SMN1):c.389A>G (p.Tyr130Cys)	SMN1	Pathogenic	no assertion criteria provided
39513	NM_000344.4(SMN1):c.388T>C (p.Tyr130His)	SMN1	Pathogenic	no assertion criteria provided
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
634942	NM_000344.4(SMN1):c.724-2A>G	SMN1	Pathogenic	criteria provided, single submitter
634947	NM_000344.4(SMN1):c.399_402del (p.Glu134fs)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
9165	NM_000344.4(SMN1):c.785G>T (p.Ser262Ile)	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
9169	NG_008691.1:g.(32498_32055)(33073?)del	SMN1	Pathogenic	no assertion criteria provided
9170	NM_000344.4(SMN1):c.834+6T>G	SMN1	Pathogenic	no assertion criteria provided
9172	NM_000344.4(SMN1):c.131A>T (p.Asp44Val)	SMN1	Pathogenic	no assertion criteria provided
9173	NM_000344.4(SMN1):c.305G>A (p.Trp102Ter)	SMN1	Pathogenic	criteria provided, single submitter
9176	NM_000344.4(SMN1):c.283G>C (p.Gly95Arg)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
9178	NM_000344.4(SMN1):c.784A>G (p.Ser262Gly)	SMN1	Pathogenic	no assertion criteria provided
39514	NC_000005.10:g.(?70924941)(70966375_?)del	SMN1-AS1	Pathogenic	no assertion criteria provided
3239631	NM_000344.4(SMN1):c.347T>C (p.Ile116Thr)	SMN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239632	NM_000344.4(SMN1):c.766G>T (p.Asp256Tyr)	SMN1	Likely pathogenic	criteria provided, single submitter
3239712	NM_000344.4(SMN1):c.808A>G (p.Ser270Gly)	SMN1	Likely pathogenic	criteria provided, single submitter
870142	NM_000344.4(SMN1):c.379T>C (p.Tyr127His)	SMN1	Likely pathogenic	no assertion criteria provided
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
7962	NM_017411.4(SMN2):c.859G>C (p.Gly287Arg)	SMN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2113655	NM_000344.4(SMN1):c.841A>G (p.Arg281Gly)	SMN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3239717	NM_000344.4(SMN1):c.835-18_835-15del	SMN1	Uncertain significance	criteria provided, single submitter
4075817	NM_000344.4(SMN1):c.80A>C (p.Gln27Pro)	SMN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 8 · 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
SMN2	Moderate	Autosomal recessive	spinal muscular atrophy, type III

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
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

Cohort genes → proteins

3 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMN1	HGNC:11117	ENSG00000172062	Q16637	Survival motor neuron protein	gencc,clinvar
SMN2	HGNC:11118	ENSG00000205571	Q16637	Survival motor neuron protein	gencc,clinvar
SMN1-AS1	HGNC:58151	ENSG00000285204		SMN1 antisense RNA 1	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.
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMN1	Other/Unknown	no		Tudor, SMN_Tudor, Smn1
SMN2	Other/Unknown	no		Tudor, SMN_Tudor, Smn1
SMN1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
endocervix	1
ganglionic eminence	1
colonic epithelium	1
endometrium	1
smooth muscle tissue	1
bone marrow	1
bone marrow cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMN1	134		marker	ventricular zone, ganglionic eminence, endocervix
SMN2	134		marker	colonic epithelium, endometrium, smooth muscle tissue
SMN1-AS1	107		yes	bone marrow cell, ventricular zone, bone marrow

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMN1	3,595
SMN2	3,595
SMN1-AS1	0

Intra-cohort edges

A	B	Sources
SMN1	SMN2	biogrid_interaction, intact

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMN1	Q16637	15
SMN2	Q16637	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 evidence-associated genes (2 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 2 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	634.4×	2e-05	SMN1, SMN2
SARS-CoV-2 modulates host translation machinery	2	223.9×	7e-05	SMN1, SMN2
snRNP Assembly	2	211.5×	7e-05	SMN1, SMN2
SARS-CoV-2-host interactions	2	119.0×	2e-04	SMN1, SMN2
SARS-CoV-2 Infection	2	80.4×	3e-04	SMN1, SMN2
SARS-CoV Infections	2	55.4×	5e-04	SMN1, SMN2
Metabolism of RNA	2	41.7×	8e-04	SMN1, SMN2
Viral Infection Pathways	2	30.8×	0.001	SMN1, SMN2
Infectious disease	2	24.8×	0.002	SMN1, SMN2
Disease	2	13.1×	0.006	SMN1, SMN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	2	1532.0×	2e-06	SMN1, SMN2
spliceosomal complex assembly	2	601.9×	4e-06	SMN1, SMN2
spliceosomal snRNP assembly	2	581.1×	4e-06	SMN1, SMN2
nervous system development	2	45.9×	5e-04	SMN1, SMN2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 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
SMN1	BEPRIDIL
SMN2	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMN1	352	4
SMN2	352	4
SMN1-AS1	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): 0.

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

Symbol	Assays	Type breakdown
SMN1	29	Binding:23, Functional:6
SMN2	29	Binding:23, Functional:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SMN1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMN1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 20.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	12
PHASE2	5
PHASE3	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
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
NCT06421831	PHASE1/PHASE2	RECRUITING	Evaluation of Safety and Efficacy of Gene Therapy Drug in the Treatment of Spinal Muscular Atrophy (SMA) Type 3 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
NCT02227823	PHASE2	COMPLETED	Safety and Efficacy Study of Pyridostigmine on Patients With Spinal Muscular Atrophy Type 3
NCT02941328	PHASE2	COMPLETED	SPACE Trial: Pyridostigmine vs Placebo in SMA Types 2, 3 and 4
NCT03819660	PHASE2	TERMINATED	Long Term Safety of Amifampridine Phosphate in Spinal Muscular Atrophy 3
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
NCT06562283	Not specified	RECRUITING	Evaluation of the Reproducibility of a Fatigability Test Fitted to Patients With Spinal Muscular Atrophy
NCT06839469	Not specified	RECRUITING	Establishing Walking-related Digital Biomarkers in Rare Childhood Onset Progressive Neuromuscular Disorders
NCT07400198	Not specified	RECRUITING	Gait and Bone Health in SMA
NCT02895789	Not specified	COMPLETED	Oxidative Capacity and Exercise Tolerance in Ambulatory SMA
NCT03056144	Not specified	TERMINATED	Whole Body Vibration Therapy in Children With Spinal Muscular Atrophy
NCT04193085	Not specified	COMPLETED	Wearable Technology to Assess Gait Function in SMA and DMD
NCT04907162	Not specified	COMPLETED	Musculoskeletal Nociceptive Pain in Participants With Neuromuscular Disorders
NCT05272969	Not specified	UNKNOWN	Pompe & Pain - Study to Assess Nociceptive Pain in Adult Patients With Pompe Disease
NCT05430113	Not specified	COMPLETED	Spinal Cord Stimulation in Spinal Muscular Atrophy
NCT05544994	Not specified	UNKNOWN	The Effect of Aerobic Exercise Training in Patients With Type III Spinal Muscular Atrophy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PYRIDOSTIGMINE	4	3
NUSINERSEN	4	1
RISDIPLAM	4	1
APITEGROMAB	3	4