Spinal muscular atrophy, type 1

Summary

Spinal muscular atrophy, type 1 (MONDO:0009669) is a disease caused by SMN1 (GenCC Definitive), with 3 cohort genes and 11 clinical trials. Top therapeutic interventions include onasemnogene abeparvovec.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal gene: SMN1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 35
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.26	Europe	Not yet validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spinal muscular atrophy, type 1
Mondo ID	MONDO:0009669
OMIM	253300
Orphanet	83330
DOID	DOID:13137
ICD-11	915903258
NCIT	C98670
SNOMED CT	64383006
UMLS	C5848259
MedGen	1845578
GARD	0007883
NORD	1844
Is cancer (heuristic)	no

Also known as: infantile muscular atrophy · infantile spinal muscular atrophy · proximal spinal muscular atrophy, type 1 · severe infantile spinal muscular atrophy · SMA type 1 · SMA type I · SMA-I · SMA1 · SMNI · spinal muscular atrophies of childhood · spinal muscular atrophy 1 · spinal muscular atrophy, type I · spinal muscular atrophy-1 · survival motor neuron spinal muscular atrophy · Werdnig Hoffmann disease · Werdnig-Hoffman disease · Werdnig-Hoffmann Disease · Werdnig-Hoffmann disease

Data availability: 35 ClinVar variants · 4 GenCC gene-disease records · 48 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 1

Related subtypes (5): spinal muscular atrophy, type III, 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

35 retrieved; paginated sample, class counts are floors:

18 pathogenic, 5 likely pathogenic, 4 uncertain significance, 4 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699219	NM_000344.4(SMN1):c.549del (p.Lys184fs)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
2571610	NM_000344.4(SMN1):c.835-8_835-5delinsG	SMN1	Pathogenic	no assertion criteria provided
2690718	NM_000344.4(SMN1):c.597dup (p.Met200fs)	SMN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239629	NM_000344.4(SMN1):c.245_267del (p.Lys82fs)	SMN1	Pathogenic	criteria provided, single submitter
3239716	NM_000344.4(SMN1):c.827A>G (p.Tyr276Cys)	SMN1	Pathogenic	criteria provided, single submitter
4057250	NM_000344.4(SMN1):c.91dup (p.Ser31fs)	SMN1	Pathogenic	no assertion criteria provided
431179	NC_000005.10:g.70946066_70946176del	SMN1	Pathogenic	no assertion criteria provided
586627	NM_000344.4(SMN1):c.770_780dup (p.Gly261fs)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
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
634947	NM_000344.4(SMN1):c.399_402del (p.Glu134fs)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
692109	NM_000344.4(SMN1):c.82-2548_723+515del	SMN1	Pathogenic	criteria provided, single submitter
805485	NM_000344.4(SMN1):c.469C>T (p.Gln157Ter)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
9166	NM_000344.4(SMN1):c.815A>G (p.Tyr272Cys)	SMN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9167	NM_000344.4(SMN1):c.836G>T (p.Gly279Val)	SMN1	Pathogenic	no assertion criteria provided
9171	NM_000344.4(SMN1):c.439_443del (p.Glu147fs)	SMN1	Pathogenic	no assertion criteria provided
9177	NM_000344.4(SMN1):c.332C>G (p.Ala111Gly)	SMN1	Pathogenic	criteria provided, single submitter
9179	NM_000344.4(SMN1):c.346A>T (p.Ile116Phe)	SMN1	Pathogenic	criteria provided, multiple submitters, no conflicts
9180	NM_000344.4(SMN1):c.406C>G (p.Gln136Glu)	SMN1	Pathogenic	no assertion criteria provided
973541	NM_000344.4(SMN1):c.724_885del (p.Ile242_Ter295del)	SMN1	Pathogenic	criteria provided, single submitter
983311	GRCh37/hg19 5q13.2(chr5:70247768-70248841)x1	SMN1	Pathogenic	no assertion criteria provided
983312	GRCh37/hg19 5q13.2(chr5:70247768-70248841)x1	SMN1	Pathogenic	no assertion criteria provided
2664372	NM_000344.4(SMN1):c.268C>T (p.Gln90Ter)	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
3897011	NM_000344.4(SMN1):c.844C>T (p.Gln282Ter)	SMN1	Likely pathogenic	criteria provided, single submitter
929467	NM_000344.4(SMN1):c.280G>T (p.Val94Phe)	SMN1	Likely pathogenic	criteria provided, single submitter
929483	NM_000344.4(SMN1):c.*3+3A>T	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
586628	NM_000344.4(SMN1):c.840C>T (p.Phe280=)	SMN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 9 · 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
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
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

3 cohort genes, 2 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	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 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.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

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
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom

Expression context

Cohort genes with no expression data: 0.

3 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
endocervix	1
ganglionic eminence	1
ventricular zone	1
colonic epithelium	1
endometrium	1
smooth muscle tissue	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	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
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMN1	3,595
SMN2	3,595
SPTAN1	3,083

Intra-cohort edges

A	B	Sources
SMN1	SMN2	biogrid_interaction, intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMN1	Q16637	15
SMN2	Q16637	15
SPTAN1	Q13813	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 3 evidence-associated genes (3 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 3 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	423.0×	3e-04	SMN1, SMN2
SARS-CoV-2 modulates host translation machinery	2	149.3×	0.001	SMN1, SMN2
snRNP Assembly	2	141.0×	0.001	SMN1, SMN2
SARS-CoV-2-host interactions	2	79.3×	0.002	SMN1, SMN2
SARS-CoV-2 Infection	2	53.6×	0.004	SMN1, SMN2
SARS-CoV Infections	2	37.0×	0.008	SMN1, SMN2
Metabolism of RNA	2	27.8×	0.011	SMN1, SMN2
Caspase-mediated cleavage of cytoskeletal proteins	1	317.2×	0.016	SPTAN1
Viral Infection Pathways	2	20.5×	0.016	SMN1, SMN2
Infectious disease	2	16.6×	0.022	SMN1, SMN2
Apoptotic cleavage of cellular proteins	1	158.6×	0.023	SPTAN1
Nephrin family interactions	1	158.6×	0.023	SPTAN1
Apoptotic execution phase	1	158.6×	0.023	SPTAN1
Interaction between L1 and Ankyrins	1	122.8×	0.027	SPTAN1
Sensory processing of sound	1	102.9×	0.029	SPTAN1
RHOV GTPase cycle	1	95.2×	0.029	SPTAN1
RHOU GTPase cycle	1	92.8×	0.029	SPTAN1
NCAM signaling for neurite out-growth	1	90.6×	0.029	SPTAN1
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.036	SPTAN1
Apoptosis	1	56.0×	0.039	SPTAN1
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.039	SPTAN1
Disease	2	8.7×	0.039	SMN1, SMN2
Programmed Cell Death	1	48.8×	0.041	SPTAN1
Cell-Cell communication	1	45.9×	0.041	SPTAN1
ER to Golgi Anterograde Transport	1	44.3×	0.041	SPTAN1
MAPK1/MAPK3 signaling	1	43.8×	0.041	SPTAN1
L1CAM interactions	1	40.1×	0.043	SPTAN1
COPI-mediated anterograde transport	1	36.6×	0.045	SPTAN1
MAPK family signaling cascades	1	34.3×	0.045	SPTAN1
Transport to the Golgi and subsequent modification	1	34.3×	0.045	SPTAN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	1021.3×	7e-06	SMN1, SMN2
spliceosomal complex assembly	2	401.2×	2e-05	SMN1, SMN2
spliceosomal snRNP assembly	2	387.4×	2e-05	SMN1, SMN2
nervous system development	2	30.6×	0.002	SMN1, SMN2
actin filament capping	1	510.7×	0.002	SPTAN1
actin cytoskeleton organization	1	26.4×	0.037	SPTAN1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 0

Druggability breadth: 3 of 3 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
SMN2	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMN1	352	4
SMN2	352	4
SPTAN1	1	2

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
SPTAN1	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	SPTAN1
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: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07554924	PHASE1/PHASE2	NOT_YET_RECRUITING	A Phase I/II Clinical Study to Evaluate SKG0201 Injection in Subjects With Spinal Muscular Atrophy Type I
NCT02122952	PHASE1	COMPLETED	Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1
NCT03421977	Not specified	ACTIVE_NOT_RECRUITING	Long-Term Follow-up Study for Patients From AVXS-101-CL-101
NCT05954455	Not specified	RECRUITING	Exploring Bulbar Function, Speech And Communication Development in SMA Type 1
NCT06152302	Not specified	RECRUITING	Test of Aquatic Mobility of SMA Infants
NCT06191354	Not specified	ACTIVE_NOT_RECRUITING	A Clinical Study Evaluating the Safety and Efficacy of SKG0201 Injection in Patients With Spinal Muscular Atrophy Type 1
NCT06562283	Not specified	RECRUITING	Evaluation of the Reproducibility of a Fatigability Test Fitted to Patients With Spinal Muscular Atrophy
NCT07596277	Not specified	NOT_YET_RECRUITING	Exploring Lived Experiences of Families of Children With Spinal Muscular Atrophy(SMA) Type 1 Regarding Feeding and Communication
NCT01862042	Not specified	COMPLETED	Palliative Care in Spinal Muscular Atrophy (SMA) 1
NCT03395795	Not specified	COMPLETED	Trial Evaluating the Interest of Noninvasive Ventilation in NAVA Mode in Respiratory Decompensations Children With Infantile Spinal Muscular Atrophy Type II
NCT06256887	Not specified	UNKNOWN	Sleep Spindles Organization as an Early Neural Marker of Neuromotor Outcome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ONASEMNOGENE ABEPARVOVEC	4	1