X-linked distal spinal muscular atrophy type 3

Summary

X-linked distal spinal muscular atrophy type 3 (MONDO:0010338) is a disease caused by ATP7A (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP7A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,733

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked distal spinal muscular atrophy type 3
Mondo ID	MONDO:0010338
MeSH	C564506
OMIM	300489
Orphanet	139557
DOID	DOID:0111196
SNOMED CT	766764008
UMLS	C1845359
MedGen	335168
GARD	0016957
Is cancer (heuristic)	no

Also known as: ATP7A spinal muscular atrophy · ATP7A-related distal motor neuropathy · DSMAX · SMAX3 · spinal muscular atrophy caused by mutation in ATP7A · spinal muscular atrophy, distal, X-linked 3 · spinal muscular atrophy, distal, X-linked 3, X-linked recessive · spinal muscular atrophy, distal, X-linked type 3 · X-linked dHMN type 3 · X-linked dHMN3 · X-linked distal hereditary motor neuropathy type 3 · X-linked dSMA type 3 · X-linked dSMA3

Data availability: 1,733 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked distal spinal muscular atrophy type 3

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

600 retrieved; paginated sample, class counts are floors:

303 likely benign, 134 uncertain significance, 65 likely pathogenic, 54 conflicting classifications of pathogenicity, 25 benign, 16 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073823	NC_000023.10:g.(?77270139)(77271398_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1073824	NC_000023.10:g.(?77227108)(77258743_?)del	ATP7A	Pathogenic	criteria provided, single submitter
11784	NM_000052.7(ATP7A):c.2938C>T (p.Arg980Ter)	ATP7A	Pathogenic	criteria provided, multiple submitters, no conflicts
11793	NM_000052.7(ATP7A):c.601C>T (p.Arg201Ter)	ATP7A	Pathogenic	criteria provided, multiple submitters, no conflicts
11795	NM_000052.7(ATP7A):c.4156C>T (p.Pro1386Ser)	ATP7A	Pathogenic	criteria provided, single submitter
1351221	NM_000052.7(ATP7A):c.2186G>A (p.Trp729Ter)	ATP7A	Pathogenic	criteria provided, single submitter
1356350	NC_000023.10:g.(?77264993)(77268389_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1365570	NC_000023.10:g.(?77243718)(77245474_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1403273	NM_000052.7(ATP7A):c.802C>T (p.Gln268Ter)	ATP7A	Pathogenic	criteria provided, single submitter
1458814	NC_000023.10:g.(?77275721)(77279056_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1459436	NC_000023.10:g.(?77227108)(77227268_?)del	ATP7A	Pathogenic	criteria provided, single submitter
1460210	NM_000052.7(ATP7A):c.3560G>A (p.Trp1187Ter)	ATP7A	Pathogenic	criteria provided, single submitter
1685559	NM_000052.7(ATP7A):c.437del (p.Leu146fs)	ATP7A	Pathogenic	criteria provided, single submitter
1685560	NM_000052.7(ATP7A):c.1668_1680del (p.Ile556fs)	ATP7A	Pathogenic	criteria provided, single submitter
1685561	NM_000052.7(ATP7A):c.3659-1G>A	ATP7A	Pathogenic	criteria provided, single submitter
1685562	NM_000052.7(ATP7A):c.3802-1G>A	ATP7A	Pathogenic	criteria provided, single submitter
1726836	NM_000052.7(ATP7A):c.412C>T (p.Gln138Ter)	ATP7A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1345204	NM_000052.7(ATP7A):c.2172+5G>A	ATP7A	Likely pathogenic	criteria provided, single submitter
1496499	NM_000052.7(ATP7A):c.2498+2T>G	ATP7A	Likely pathogenic	criteria provided, single submitter
1685249	NM_000052.7(ATP7A):c.2180G>A (p.Gly727Glu)	ATP7A	Likely pathogenic	criteria provided, single submitter
1685250	NM_000052.7(ATP7A):c.2916+3A>T	ATP7A	Likely pathogenic	criteria provided, single submitter
1687717	NM_000052.7(ATP7A):c.1544-1G>C	ATP7A	Likely pathogenic	no assertion criteria provided
1723931	NM_000052.7(ATP7A):c.3667_3669delinsA (p.Cys1223fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1723955	NM_000052.7(ATP7A):c.753_755delinsA (p.Asp251fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1723972	NM_000052.7(ATP7A):c.3793_3794del (p.Ala1265fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724000	NM_000052.7(ATP7A):c.338_339del (p.Val113fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724030	NM_000052.7(ATP7A):c.526A>T (p.Lys176Ter)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724063	NM_000052.7(ATP7A):c.1296_1297del (p.Gly433fs)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724086	NM_000052.7(ATP7A):c.2110C>T (p.Gln704Ter)	ATP7A	Likely pathogenic	criteria provided, single submitter
1724174	NM_000052.7(ATP7A):c.420_423delinsCTGTCTCTTATACACAT (p.Lys140fs)	ATP7A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · 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
ATP7A	Definitive	X-linked	X-linked distal spinal muscular atrophy type 3	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP7A	Orphanet:139557	X-linked distal spinal muscular atrophy type 3
ATP7A	Orphanet:198	Occipital horn syndrome
ATP7A	Orphanet:388	Hirschsprung disease
ATP7A	Orphanet:565	Menkes disease

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
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd

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
buccal mucosa cell	1
trabecular bone tissue	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP7A	3,901

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP7A	Q04656	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Ion influx/efflux at host-pathogen interface	1	2855.0×	0.004	ATP7A
Detoxification of Reactive Oxygen Species	1	300.5×	0.013	ATP7A
Antimicrobial peptides	1	223.9×	0.013	ATP7A
Ion transport by P-type ATPases	1	207.6×	0.013	ATP7A
Cellular response to chemical stress	1	142.8×	0.015	ATP7A
Ion channel transport	1	96.0×	0.019	ATP7A
Cellular responses to stress	1	36.8×	0.043	ATP7A
Cellular responses to stimuli	1	31.5×	0.044	ATP7A
Innate Immune System	1	25.5×	0.044	ATP7A
Transport of small molecules	1	25.1×	0.044	ATP7A
Immune System	1	13.0×	0.077	ATP7A

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
obsolete negative regulation of catecholamine metabolic process	1	8426.0×	0.002	ATP7A
obsolete L-tryptophan metabolic process	1	5617.3×	0.002	ATP7A
epinephrine metabolic process	1	5617.3×	0.002	ATP7A
copper ion export	1	5617.3×	0.002	ATP7A
obsolete tyrosine metabolic process	1	4213.0×	0.002	ATP7A
catecholamine metabolic process	1	4213.0×	0.002	ATP7A
T-helper cell differentiation	1	3370.4×	0.002	ATP7A
copper ion import	1	2407.4×	0.002	ATP7A
pyramidal neuron development	1	2106.5×	0.002	ATP7A
norepinephrine biosynthetic process	1	2106.5×	0.002	ATP7A
copper ion transport	1	1685.2×	0.002	ATP7A
serotonin metabolic process	1	1685.2×	0.002	ATP7A
norepinephrine metabolic process	1	1532.0×	0.002	ATP7A
elastic fiber assembly	1	1532.0×	0.002	ATP7A
positive regulation of melanin biosynthetic process	1	1404.3×	0.002	ATP7A
regulation of oxidative phosphorylation	1	1203.7×	0.002	ATP7A
detoxification of copper ion	1	1123.5×	0.002	ATP7A
removal of superoxide radicals	1	1053.2×	0.002	ATP7A
cerebellar Purkinje cell differentiation	1	1053.2×	0.002	ATP7A
dopamine metabolic process	1	991.3×	0.002	ATP7A
intracellular copper ion homeostasis	1	936.2×	0.002	ATP7A
central nervous system neuron development	1	802.5×	0.002	ATP7A
release of cytochrome c from mitochondria	1	702.2×	0.003	ATP7A
pigmentation	1	702.2×	0.003	ATP7A
hair follicle morphogenesis	1	495.6×	0.003	ATP7A
ATP metabolic process	1	468.1×	0.003	ATP7A
neuron cellular homeostasis	1	455.5×	0.003	ATP7A
skin development	1	443.5×	0.003	ATP7A
dendrite morphogenesis	1	432.1×	0.003	ATP7A
blood vessel remodeling	1	383.0×	0.004	ATP7A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP7A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATP7A	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	ATP7A

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)
ATP7A	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.