ATP7A

Chr X

ATPase copper transporting alpha

Also known as: DSMAX, HMNX, MK, MNK, SMAX3

NCBI Gene: 538ENSG00000165240UniProt: Q04656

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]

Primary Disease Associations & Inheritance

UniProtMenkes disease
UniProtOccipital horn syndrome
UniProtNeuronopathy, distal hereditary motor, X-linked
600
ClinVar variants
71
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— ATP7A
🧬
Gene-Disease Validity (ClinGen)
X-linked distal spinal muscular atrophy type 3 · XLModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
71 Pathogenic / Likely Pathogenic· 250 VUS of 600 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.22LOEUF
pLI 1.000
Z-score 5.47
OE 0.09 (0.04–0.22)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.53Z-score
OE missense 0.82 (0.76–0.88)
448 obs / 548.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.04–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.76–0.88)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.82
0≤1.21.6
LoF obs/exp: 4 / 42.4Missense obs/exp: 448 / 548.9Syn Z: 2.00

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic37
VUS250
Likely Benign213
Benign43
Conflicting23
34
Pathogenic
37
Likely Pathogenic
250
VUS
213
Likely Benign
43
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
22
0
34
Likely Pathogenic
25
4
8
0
37
VUS
2
228
17
3
250
Likely Benign
0
38
77
98
213
Benign
0
11
20
12
43
Conflicting
—23
Total39281144113600

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ATP7A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ATP7A-related cutis laxa/occipital Horn syndrome

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product, Decreased Gene Product Level
Skin
G2P ↗

ATP7A-related Menkes disease

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

ATP7A-related spinal muscular atrophy, distal

definitive
Monoallelic X HemizygousUndeterminedAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — ATP7A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Copper metabolism in cell death and autophagy.
Xue Q et al.·Autophagy
2023Review
Wilson's disease and other neurological copper disorders.
Bandmann O et al.·Lancet Neurol
2015Review
ATP7A-related copper transport disorders: A systematic review and definition of the clinical subtypes.
De Feyter S et al.·J Inherit Metab Dis
2023Review
Canine Copper-Associated Hepatitis.
Dirksen K et al.·Vet Clin North Am Small Anim Pract
2017Review
Targeting ATP7A-Dependent Copper Metabolic Homeostasis Induces Cuproptosis and Suppresses the Progression of Mutant KRAS-Driven Lung Cancer.
Zhao J et al.·Cancer Res
2025
Small amounts of functional ATP7A protein permit mild phenotype.
Møller LB·J Trace Elem Med Biol
2015Review
Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.
Olsen CG et al.·Amyotroph Lateral Scler Frontotemporal Degener
2024
ATP7A-related copper transport diseases-emerging concepts and future trends.
Kaler SG·Nat Rev Neurol
2011Review
Wilson disease.
Harada M·Med Electron Microsc
2002Review
The contribution of copper efflux transporters ATP7A and ATP7B to chemoresistance and personalized medicine in ovarian cancer.
Lukanović D et al.·Biomed Pharmacother
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Systemic Lupus ErythematosusCAR-T Cell Therapy

Study of Therapeutic Efficacy of Anti-CD19 CAR-T Cells in Refractory Systemic Lupus Erythematosus

ACTIVE NOT RECRUITING
NCT06222853Phase PHASE1The Children's Hospital of Zhejiang University School of MedicineStarted 2024-02-10
anti-CD19-CAR-T cells
Invasive PreNatal Diagnosis in a Context of Family History of Single-gene Disorders, IncludingSickle Cell DiseaseCystic Fibrosis

Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders

RECRUITING
NCT06147414Assistance Publique - Hôpitaux de ParisStarted 2024-10-23
Blood sample

External Resources

Links to major genomics databases and tools