ATP7A
protein-codingATPase copper transporting alpha, the group of ATPase copper transporting
Gene summary
This gene encodes a transmembrane protein that functions in copper transport across membranes. This protein is localized to the trans Golgi network, where it is predicted to supply copper to copper-dependent enzymes in the secretory pathway. It relocalizes to the plasma membrane under conditions of elevated extracellular copper, and functions in the efflux of copper from cells. Mutations in this gene are associated with Menkes disease, X-linked distal spinal muscular atrophy, and occipital horn syndrome. Alternatively-spliced transcript variants have been observed. [provided by RefSeq, Aug 2013]
- MNK
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~139.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010338
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010651
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010338
Submitter: ClinGen
ATP7A encodes the copper-transporting ATPase alpha. In basal conditions, it is in the trans-Golgi Network (TGV) and transports copper to the cuproenzymes (copper metalloenzymes). However, in elevated copper concentrations, it localizes to the plasma membrane and facilitates the export of excess copper from the cells through exocytosis (Møller et al., PMID: 19501626). The gene was first mapped to chrXq13.3 in 1993 (Vulpe et al, PMID: 8490659; Mercer et al., PMID: 8490647; Chelly et al., PMID: 8490646) in patients with Menkes disease (MIM:309400) due to a loss of function mechanism in ATP7A. Partial loss of function is associated with occipital horn syndrome (MIM: 304150). Subnormal serum copper levels and early age of onset are characteristic for both phenotypes. In 2009, ATP7A was first reported in relation to X-linked recessive distal spinal muscular atrophy in two families (Kennerson et al., PMID: 20170900). These patients present during adulthood with progressive distal muscle weakness and atrophy without clinical or biochemical characteristics of systemic copper deficiency. Some patients show dysautonomic features (Gualandi et al., PMID: 31558336; Fradin et al., PMID: 33137485). Per criteria outlined by the ClinGen Lumping and Splitting Working group, we found a difference in molecular mechanism and phenotypic variability but no difference in inheritance pattern in the association of ATP7A with distal spinal muscular atrophy. Therefore, the following diseases entities have been split into the three before-mentioned entities: Menkes disease, Occipital Horn Syndrome and distal spinal muscular atrophy. Four different missense variants were reported of which three segregated in families (Kennerson et al., PMID: 20170900; Gualandi et al., PMID: 31558336) and one was sporadic (Fradin et al., PMID: 33137485). Two of these variants occur in the carboxyl half of the ATP7A protein, are highly conserved and absent in control populations (Kennerson et al., PMID: 20170900). Two other variants were predicted to be deleterious in in silico evaluations and were absent in control populations (Gualandi et al., PMID: 31558336; Fradin et al., PMID: 33137485). The gene-disease association is also supported by experimental evidence. Patient (Atp7A-T994I)-derived fibroblasts show reduced trans-Golgi-localization of ATP7A and more diffuse signals in cultured cells. Immunoprecipitation assays identified p97/VCP as an interaction protein (Yi et al., PMID: 22210628). Two mouse models were generated, a knock-in mouse (Atp7a-T994I) and a transgenic mouse (Atp7aMN/Y), with contradictory results. Herein the knock-in model showed no altered motor abilities or histological manifestations of acute or chronic neuropathy (Perez-Siles et al., PMID: 27293072), whereas the transgenic model exhibited progressive motor abnormalities and age-dependent loss of motor neuron cell bodies and denervation of the neuromuscular junction (Hodgkinson et al., PMID: 25639447). The mechanism of pathogenicity appears to be partial loss of function, altered protein-to-protein interaction (cfr. P97/VCP), and intracellular trafficking. In summary, ATP7A is moderately associated with x-linked distal spinal muscular atrophy. While more evidence is needed to establish this relationship definitely, no convincing contradictory evidence has emerged. **Recuration Update**: One additional publication was curated with two affected siblings with ATP7A-related distal motor neuropathy/occipital horn syndrome phenotype. Writzl et al. (2025; PMID: 41010022) reported two affected Slovenian brothers with an overlapping ATP7A-related distal motor neuropathy/occipital horn syndrome phenotype. Both were hemizygous for the novel splice-site variant NM_000052.7:c.1544-2A>T. The proband had developmental delay, intellectual disability, chronic diarrhea, progressive distal motor neuropathy, steppage gait, occipital horns, and mildly reduced copper/ceruloplasmin. His brother had childhood diarrhea and hyperhidrosis followed by adolescent-onset progressive distal weakness, muscle atrophy, areflexia, peroneal gait, tremor, ataxia, and occipital horns, without sensory loss or cognitive impairment. RNA studies from the proband showed two abnormal ATP7A transcripts and no normal transcript: complete exon 6 skipping predicted to cause frameshift/NMD, and partial exon 6 deletion resulting in an in-frame loss of 14 amino acids. The variant was present in both affected brothers, but the unaffected mother declined testing, so inheritance and de novo status remain unknown. For ClinGen scoring, 1.0 case-level point was assigned to the family.
Inheritance Pattern: XL
Disease ID:MONDO:0010338
Submitter: G2P
Inheritance Pattern: XLR
Disease ID:MONDO:0010651
Submitter: Natera
Inheritance Pattern: XL
Disease ID:MONDO:0010651
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010572
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010338
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010651
Submitter: ClinGen
*ATP7A* was first reported in relation to X-linked Menkes disease in 1994 (Kaler et al., PMID: 7842019). The *ATP7A* gene encodes a transmembrane protein involved in intracellular copper ion homeostasis. Menkes disease is characterized by short stature, microcephaly, osteoporosis, characteristic hair texture and color, skin laxity, hypotonia, intellectual disability, and seizures. Sixteen variants (missense, nonsense, frameshift, splice) that have been reported in 16 probands in 4 publications (PMIDs: 7977350, 8981948, 21738351, 25771438) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *ATP7A* is highly constrained for loss-of-function variants (gnomAD v2.1.1). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including functional alteration in patient cells and a mouse model (PMIDs: 16488577, 17483305). In summary, there is definitive evidence supporting the relationship between *ATP7A* and X-linked Menkes disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 7, 2018 (SOP Version 5). As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
Inheritance Pattern: AD
Disease ID:MONDO:0018309
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010338
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010572
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010651
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010572
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010651
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010572
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0010338
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010651
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Dermatologic; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Renal
Intervention: Biochemical; Renal
Rationale: With early diagnosis, daily copper injections may be beneficial (SQ injections before 10 days of life have been reported as resulting in improvement of neurologic outcome); Individuals may be prone to urinary tract infections, and measures such as antibiotic prophylaxis may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATP7A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000052.7. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 19 | 452 | 20 | 491 | ||
| missense | 11 | 34 | 707 | 307 | 36 | 1095 |
| nonsense | 46 | 24 | 23 | 93 | ||
| start loss | 1 | 1 | ||||
| frameshift | 52 | 59 | 56 | 167 | ||
| splice donor/acceptor (+/-2bp) | 20 | 15 | 26 | 61 | ||
| Total | 129 | 132 | 832 | 759 | 56 | 1908 |
Highest pathogenic variant AF is 0.0000018215119
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000043.4 | 22 | MANE Select | |
| Ensembl | ENSP00000345728.6 | 22 | MANE Select | |
| RefSeq | NP_001269153.1 | 21 | Standard | |
| Ensembl | ENSP00000343026.6 | 23 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| atp7a | Danio rerio | Structure: melanocyte Quality: intensity abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mineral absorption - Homo sapiens (human)
- Platinum Pathway, Pharmacokinetics/Pharmacodynamics
- Copper homeostasis
- Ion influx/efflux at host-pathogen interface
- Ion channel transport
Biological Process
- blood vessel development
- in utero embryonic development
- liver development
- blood vessel remodeling
- regulation of oxidative phosphorylation
Molecular Function
- copper-exporting ATPase activity
- copper ion transmembrane transporter activity
- copper ion binding
- protein binding
- ATP binding
Cellular Component
- nucleus
- late endosome
- endoplasmic reticulum
- Golgi apparatus
- trans-Golgi network
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000341514
- Coding exons
- 22
- Length
- 139699
- Individuals with no LoFs
- 125722
- Homozygous LoFs
- 3
- Heterozygous LoFs
- 5
- Defined
- 125730
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.53 | 448 | 549 | 0.816 | 0.0000395 | 9789 |
| Missense (PolyPhen) | 143 | 234.17 | 0.61068 | 4197 | ||
| Synonymous | 2.00 | 161 | 197 | 0.819 | 0.0000144 | 3053 |
| Loss of Function | 5.47 | 4 | 42.4 | 0.0942 | 0.00000324 | 761 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00022 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000037 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May supply copper to copper-requiring proteins within the secretory pathway, when localized in the trans-Golgi network. Under conditions of elevated extracellular copper, it relocalized to the plasma membrane where it functions in the efflux of copper from cells.;
- Disease
- DISEASE: Menkes disease (MNKD) [MIM:309400]: An X-linked recessive disorder of copper metabolism characterized by generalized copper deficiency. MNKD results in progressive neurodegeneration and connective-tissue disturbances: focal cerebral and cerebellar degeneration, early growth retardation, peculiar hair, hypopigmentation, cutis laxa, vascular complications and death in early childhood. The clinical features result from the dysfunction of several copper-dependent enzymes. A mild form of the disease has been described, in which cerebellar ataxia and moderate developmental delay predominate. {ECO:0000269|PubMed:10079817, ECO:0000269|PubMed:10319589, ECO:0000269|PubMed:10401004, ECO:0000269|PubMed:11241493, ECO:0000269|PubMed:11350187, ECO:0000269|PubMed:15981243, ECO:0000269|PubMed:21667063, ECO:0000269|PubMed:22992316, ECO:0000269|PubMed:7977350, ECO:0000269|PubMed:8981948}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Occipital horn syndrome (OHS) [MIM:304150]: An X-linked recessive disorder of copper metabolism. Common features are unusual facial appearance, skeletal abnormalities, chronic diarrhea and genitourinary defects. The skeletal abnormalities include occipital horns, short, broad clavicles, deformed radii, ulnae and humeri, narrowing of the rib cage, undercalcified long bones with thin cortical walls and coxa valga. {ECO:0000269|PubMed:11431706, ECO:0000269|PubMed:17108763, ECO:0000269|PubMed:21667063, ECO:0000269|PubMed:9246006}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Distal spinal muscular atrophy, X-linked, 3 (DSMAX3) [MIM:300489]: A neuromuscular disorder. Distal spinal muscular atrophy, also known as distal hereditary motor neuronopathy, represents a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. {ECO:0000269|PubMed:20170900}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0197
- RVIS EVS
- 0.41
- RVIS percentile EVS
- 76.49
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.491
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |