ATP7A

Summary

ATP7A (ATPase copper transporting alpha, HGNC:869) is a protein-coding gene on chromosome Xq21.1, encoding Copper-transporting ATPase 1 (Q04656). ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 538 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Menkes disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 2,363 total — 157 pathogenic, 118 likely-pathogenic
• Phenotypes (HPO): 178
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000052

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:869
Approved symbol	ATP7A
Name	ATPase copper transporting alpha
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000165240
Ensembl biotype	protein_coding
OMIM	300011
Entrez	538

Gene structure

Transcript identifiers

Ensembl transcripts: 57 — 36 protein_coding, 15 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000341514, ENST00000343533, ENST00000642523, ENST00000642651, ENST00000645094, ENST00000645454, ENST00000682475, ENST00000682742, ENST00000684798, ENST00000685033, ENST00000685208, ENST00000685264, ENST00000685434, ENST00000685885, ENST00000686033, ENST00000686050, ENST00000686133, ENST00000686255, ENST00000686416, ENST00000686464, ENST00000686480, ENST00000686515, ENST00000686543, ENST00000686560, ENST00000686688, ENST00000686896, ENST00000686999, ENST00000687082, ENST00000687086, ENST00000687325, ENST00000687416, ENST00000687599, ENST00000687628, ENST00000687984, ENST00000688165, ENST00000688249, ENST00000688338, ENST00000688746, ENST00000688889, ENST00000689083, ENST00000689514, ENST00000689530, ENST00000689541, ENST00000689649, ENST00000689731, ENST00000689767, ENST00000689872, ENST00000689891, ENST00000691152, ENST00000691456, ENST00000692110, ENST00000692729, ENST00000692908, ENST00000693051, ENST00000693167, ENST00000693387, ENST00000693398

RefSeq mRNA: 2 — MANE Select: NM_000052 NM_000052, NM_001282224

CCDS: CCDS35339, CCDS75997

Canonical transcript exons

ENST00000341514 — 23 exons

Exon	Start	End
ENSE00001091570	78046294	78050395
ENSE00001594340	78029250	78029444
ENSE00001625459	78020945	78021079
ENSE00001628072	78012879	78013112
ENSE00001633722	78009102	78009263
ENSE00001636041	77988242	77988731
ENSE00001656404	78003073	78003236
ENSE00001690695	78011176	78011252
ENSE00001694839	78020244	78020398
ENSE00001712655	77998478	77998684
ENSE00001735395	78011449	78011674
ENSE00001765102	78014662	78014753
ENSE00001791031	78015754	78015881
ENSE00001863720	77910693	77910835
ENSE00002161973	77989233	77989958
ENSE00002210530	77971621	77971761
ENSE00003716846	78045470	78045572
ENSE00003717136	78038836	78038982
ENSE00003720032	78031400	78031582
ENSE00003725729	78042585	78042788
ENSE00003737559	78043317	78043434
ENSE00003748303	78040591	78040733
ENSE00003754662	78033605	78033821

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 89.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.4042 / max 278.7995, expressed in 1728 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196777	9.4042	1728

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	89.34	gold quality
trabecular bone tissue	UBERON:0002483	88.09	gold quality
upper leg skin	UBERON:0004262	86.31	gold quality
germinal epithelium of ovary	UBERON:0001304	85.23	gold quality
corpus epididymis	UBERON:0004359	85.11	gold quality
tibia	UBERON:0000979	84.76	gold quality
calcaneal tendon	UBERON:0003701	83.40	gold quality
parietal pleura	UBERON:0002400	83.37	gold quality
visceral pleura	UBERON:0002401	83.22	gold quality
pleura	UBERON:0000977	83.09	gold quality
skin of hip	UBERON:0001554	82.32	gold quality
hair follicle	UBERON:0002073	82.23	gold quality
upper arm skin	UBERON:0004263	81.99	gold quality
cranial nerve II	UBERON:0000941	81.58	gold quality
mucosa of paranasal sinus	UBERON:0005030	81.34	gold quality
choroid plexus epithelium	UBERON:0003911	81.30	gold quality
caput epididymis	UBERON:0004358	81.00	gold quality
adrenal tissue	UBERON:0018303	80.67	gold quality
epithelial cell of pancreas	CL:0000083	80.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.38	gold quality
cauda epididymis	UBERON:0004360	80.30	gold quality
secondary oocyte	CL:0000655	80.20	gold quality
bone marrow	UBERON:0002371	80.07	gold quality
oral cavity	UBERON:0000167	79.91	gold quality
epithelium of mammary gland	UBERON:0003244	79.82	gold quality
seminal vesicle	UBERON:0000998	79.73	gold quality
blood vessel layer	UBERON:0004797	79.38	gold quality
oviduct epithelium	UBERON:0004804	79.37	gold quality
pigmented layer of retina	UBERON:0001782	79.32	gold quality
mammalian vulva	UBERON:0000997	79.26	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	3351.13
E-CURD-114	yes	10.81
E-ANND-3	yes	6.65
E-MTAB-7606	no	147.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, ESR2, FOXC1, FOXN1, HIF1A, RUNX1, SP1, TP53, TTF1, WT1

miRNA regulators (miRDB)

182 targeting ATP7A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-570-3P	99.96	72.41	4910

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutations of the ATP7A gene lead to Menkes disease and occipital horn syndrome. Two male patients are reported with different ATP7A gene mutations and several phenotypes (PMID:11936860)
• mutations that affect the proper folding of the MNK transporter in Menkes patients may be responsive to parenteral copper therapy (PMID:12221109)
• demonstrated characterization of partial gene deletions in five patients, and in three of these determined the breakpoint sequences (PMID:12485192)
• mutated in Menkes syndrome. (PMID:12539960)
• The biochemical and genetic propreties of this enzyme, and its role in Menkes disease are examined (review) (PMID:12539963)
• Data describe the role of several conserved regions of the Menkes protein ATP7A, particularly within the putative cytosolic ATP-binding domain. (PMID:12565888)
• A copper-dependent interaction of Atox1 with the metal binding sites of menkes protein was observed (PMID:12679332)
• the route for ATP7A internalization and delivery to endosomes is Rac1-regulated, clathrin- and caveolae-independent (PMID:12812980)
• characterised the second Menkes N-terminal domain (MNKr2) structure and copper binding site (PMID:14572476)
• Results suggest that gross deletion of ATP7A is the disease-causing mutation in 14.9% of the Menkes disease patients. (PMID:14635105)
• increase in the concentration of copper in the medium (189 microM) rapidly induces a redistribution of the MNK protein from early sorting endosomes, positive for Rab5-myc protein, to late endosomes, containing the Rab7-myc protein (PMID:14644159)
• MNK can utilise both clathrin-dependent and clathrin-independent endocytosis in HeLa cells (PMID:14977365)
• copper transporting ATPase Menkes (ATP7A) is present in the syncytiotrophoblast, the cytotrophoblast and the fetal vascular endothelial cells (PMID:15135234)
• interaction between the human copper(I) chaperone, HAH1, and one of its two physiological partners, the Menkes disease protein (ATP7A), was investigated in solution using heteronuclear NMR (PMID:15670166)
• analysis of disease-causing amino acid substitutions in the conserved part of ATP7A (PMID:15981243)
• A single PDZ domain protein interacts with ATP7A. (PMID:16051599)
• A629P mutation makes the protein beta-sheet more solvent accessible, possibly resulting in an enhanced susceptibility of ATP7A to proteolytic cleavage (PMID:16083905)
• a three-domain construct of ATP7A interacts with copper(I) and copper(I)-HAH1 (PMID:16172131)
• Metal binding sequences of chimeric protein showed differences in structure and the dynamics of the binding site that may account for metal specificity. (PMID:16211579)
• Effect of copper perfusion of an isolated segment of the jejunum of ATP7A transgenic mice on the intracellular distribution of ATP7A by immunofluorescence of frozen sections. (PMID:16317117)
• Cu concentrations were reduced in most tissues of transgenic mice expressing the human Menkes gene ATP7A consistent with ATP7A playing a role in Cu efflux (PMID:16397091)
• The functional effect of a large frameshift deletion in ATP7A (including exons 3 and 4) is investigated in a patient with Menkes disease with unexpectedly mild symptoms and long survival. (PMID:16826513)
• analysis of intermolecular interactions of the third metal-binding domain of ATP7A (PMID:16873374)
• In this study, we describe the identification of glutaredoxin (GRX1) as an interacting partner of both ATP7A and ATP7B (PMID:16884690)
• Neurologic sparing in untreated occipital horn syndrome is associated with approximately 30% residual functional activity of ATP7A. (PMID:17108763)
• MNK and ATP7A are differentially regulated by the hormones insulin and oestrogen in human placental cells (PMID:17109627)
• Intestinal cells contain dispersed vesicular compartment that actively sequesters excess cytoplasmic copper. (PMID:17158254)
• We present the first reported case of Menkes disease caused by an Alu element insertion mutation in exon atp7a that interfered with splicing regulatory elements. (PMID:17178205)
• Tree males in a family with Menkes disease showed a missense mutation in an exon 8 splicing enhancer and equally reduced amounts of ATP7A transcript. (PMID:17496194)
• Review of the localization and trafficking properties of ATP7A, and the molecular signals and posttranslational interactions that govern the trafficking activities. (PMID:17531189)
• localization of ATP7A between the trans-Golgi network and the plasma membrane may be regulated by the accumulation of the adducts with HAH1, whereas the main role of domains 5 and 6 is to assist copper(I) translocation (PMID:17545667)
• A review of the structure, function and regulation of ATP7A. (PMID:17562324)
• The underlying genetic defects correlate with the molecular functions of ATP7A and the clinical expression of Menkes disease. Review. (PMID:17717039)
• A defect of the ATP7A protein leads to both a reduced transport of copper from the intestine into the circulation and into the central nervous system as well as reduced transport of copper into the Golgi apparatus (PMID:17987894)
• review of ATP7A function to maintain intracellular copper levels and incorporate copper into copper-dependent enzymes (PMID:17989919)
• The cellular accumulation of platinum and level of ATP7A mRNA may be factors affecting the cytotoxicity of cisplatin. (PMID:18030470)
• A novel deletion mutation of ATP7A gene in a Chinese family with Menkes disease. (PMID:18272047)
• These data suggest that ATP7A plays a role in removing excess copper from the mammary epithelial cells rather than supplying copper to milk. (PMID:18515074)
• Alterations in sub cellular localisation of transport proteins, ATP7A and ATP7B, may contribute to cisplatin resistance in ovarian cancer. (PMID:18565219)
• A quantitative relationship between mutated ATPase and Menkes/Wilson disease, is shown. (PMID:18688737)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp7a	ENSDARG00000003699
mus_musculus	Atp7a	ENSMUSG00000033792
rattus_norvegicus	Atp7a	ENSRNOG00000061367
drosophila_melanogaster	anne	FBGN0052000
drosophila_melanogaster	SPoCk	FBGN0052451
drosophila_melanogaster	CG45062	FBGN0266432
drosophila_melanogaster	CG45063	FBGN0266433
caenorhabditis_elegans		WBGENE00000834
caenorhabditis_elegans	pmr-1	WBGENE00004063
caenorhabditis_elegans		WBGENE00012341
caenorhabditis_elegans		WBGENE00015338
caenorhabditis_elegans		WBGENE00015660

Paralogs (21): ATP2C1 (ENSG00000017260), ATP1A2 (ENSG00000018625), ATP2B4 (ENSG00000058668), ATP2C2 (ENSG00000064270), ATP2B3 (ENSG00000067842), ATP2B1 (ENSG00000070961), ATP2A3 (ENSG00000074370), ATP12A (ENSG00000075673), ATP1A3 (ENSG00000105409), ATP4A (ENSG00000105675), ATP13A1 (ENSG00000105726), ATP7B (ENSG00000123191), ATP13A4 (ENSG00000127249), ATP1A4 (ENSG00000132681), ATP13A3 (ENSG00000133657), ATP2B2 (ENSG00000157087), ATP13A2 (ENSG00000159363), ATP1A1 (ENSG00000163399), ATP2A2 (ENSG00000174437), ATP13A5 (ENSG00000187527), ATP2A1 (ENSG00000196296)

Protein

Protein identifiers

Copper-transporting ATPase 1 — Q04656 (reviewed: Q04656)

Alternative names: Copper pump 1, Menkes disease-associated protein

All UniProt accessions (18): A0A2R8YD60, A0A8I5KPN6, A0A8I5KQ07, A0A8I5KQ62, Q04656, A0A8I5KR00, A0A8I5KST1, A0A8I5KU46, A0A8I5KVB6, A0A8I5KVT9, A0A8I5KWA8, A0A8I5KWH1, A0A8I5KXV0, A0A8I5KY05, A0A8I5KZ63, A0A8I5QJP0, A0A8I5QKR3, A0A8J9FM07

UniProt curated annotations — full annotation on UniProt →

Function. ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis. Within a catalytic cycle, acquires Cu(+) ion from donor protein on the cytoplasmic side of the membrane and delivers it to acceptor protein on the lumenal side. The transfer of Cu(+) ion across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state. Under physiological conditions, at low cytosolic copper concentration, it is localized at the trans-Golgi network (TGN) where it transfers Cu(+) ions to cuproenzymes of the secretory pathway. Upon elevated cytosolic copper concentrations, it relocalizes to the plasma membrane where it is responsible for the export of excess Cu(+) ions. May play a dual role in neuron function and survival by regulating cooper efflux and neuronal transmission at the synapse as well as by supplying Cu(+) ions to enzymes such as PAM, TYR and SOD3. In the melanosomes of pigmented cells, provides copper cofactor to TYR to form an active TYR holoenzyme for melanin biosynthesis.

Subunit / interactions. Monomer. Interacts with PDZD11. Interacts with ATOX1 and COMMD1. Interacts with TYRP1. Directly interacts with SOD3; this interaction is copper-dependent and is required for SOD3 activity.

Subcellular location. Golgi apparatus. trans-Golgi network membrane. Cell membrane. Melanosome membrane. Early endosome membrane. Cell projection. Axon. Dendrite. Postsynaptic density Cytoplasm. Cytosol Endoplasmic reticulum.

Tissue specificity. Widely expressed including in heart, brain, lung, muscle, kidney, pancreas, and to a lesser extent placenta. Expressed in fibroblasts, aortic smooth muscle cells, aortic endothelial cells and umbilical vein endothelial cells (at protein level). Expressed in cerebellum and brain cortex.

Disease relevance. Menkes disease (MNK) [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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. Neuronopathy, distal hereditary motor, X-linked (HMNX) [MIM:300489] A form of distal hereditary motor neuronopathy, 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The nucleotide-binding domain consists of a twisted six-stranded antiparallel beta-sheet flanked by two pairs of alpha-helices, forming a hydrophobic pocket that interacts with the adenine ring of ATP. The ATP binding site comprises residues located in alpha-1 and alpha-2 helices and beta-2 and beta-3 strands, which are involved in van der Waal’s interactions, and Glu-1081 which forms a hydrogen bond with the adenine ring. The heavy-metal-associated domain (HMA) coordinates a Cu(+) ion via the cysteine residues within the CXXC motif. The transfer of Cu(+) ion from ATOX1 to ATP7A involves the formation of a three-coordinate Cu(+)-bridged heterodimer where the metal is shared between the two metal binding sites of ATOX1 and ATP7A. The Cu(+) ion appears to switch between two coordination modes, forming two links with one protein and one with the other. Cisplatin, a chemotherapeutic drug, can bind the CXXC motif and hinder the release of Cu(+) ion. Contains three di-leucine motifs in the C-terminus which are required for recycling from the plasma membrane to the TGN. The di-leucine 1487-Leu-Leu-1488 motif mediates endocytosis at the plasma membrane, whereas the di-leucine 1467-Leu-Leu-1468 motif is a sorting signal for retrograde trafficking to TGN via early endosomes.

Miscellaneous. Lacks 6 transmembrane regions and 5 heavy-metal-associated (HMA) domains. Lacks the transmembrane domains 3 and 4. Expressed at a low level in several tissues of normal individuals and is the only isoform found in patients with OHS. Lacks all transmembrane regions and 5 heavy-metal-associated (HMA) domains, but has a putative nuclear localization signal attached at the N-terminus.

Similarity. Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IB subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q04656-1	4	yes
Q04656-2	1
Q04656-3	2
Q04656-4	3, 2-16
Q04656-5	5
Q04656-6	6, NML45

RefSeq proteins (2): NP_000043, NP_001269153 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001757	P_typ_ATPase	Family
IPR006121	HMA_dom	Domain
IPR006122	HMA_Cu_ion-bd	Domain
IPR008250	ATPase_P-typ_transduc_dom_A_sf	Homologous_superfamily
IPR017969	Heavy-metal-associated_CS	Conserved_site
IPR018303	ATPase_P-typ_P_site	PTM
IPR023214	HAD_sf	Homologous_superfamily
IPR023298	ATPase_P-typ_TM_dom_sf	Homologous_superfamily
IPR023299	ATPase_P-typ_cyto_dom_N	Homologous_superfamily
IPR027256	P-typ_ATPase_IB	Family
IPR036163	HMA_dom_sf	Homologous_superfamily
IPR036412	HAD-like_sf	Homologous_superfamily
IPR044492	P_typ_ATPase_HD_dom	Domain
IPR059000	ATPase_P-type_domA	Domain

Pfam: PF00122, PF00403, PF00702

Enzyme classification (BRENDA):

• EC 7.2.2.8 — P-type Cu+ transporter (BRENDA: 25 organisms, 32 substrates, 20 inhibitors, 14 Km, 4 kcat entries)
• EC 7.2.2.9 — P-type Cu2+ transporter (BRENDA: 24 organisms, 135 substrates, 11 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0009–2.02	10
ATP	0.11–0.5	5
CU+[SIDE 1]	0.0019–0.19	3
CU+	0.0004–0.0015	2
4-NITROPHENYL PHOSPHATE	9	1

Catalyzed reactions (Rhea), 1 shown:

• Cu(+)(in) + ATP + H2O = Cu(+)(out) + ADP + phosphate + H(+) (RHEA:25792)

UniProt features (248 total): sequence variant 57, strand 47, turn 27, helix 24, sequence conflict 19, modified residue 17, binding site 16, topological domain 9, transmembrane region 8, domain 7, splice variant 7, mutagenesis site 3, short sequence motif 2, glycosylation site 2, chain 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
3CJK	X-RAY DIFFRACTION	1.8
5T7L	X-RAY DIFFRACTION	2.83
1AW0	SOLUTION NMR
1KVI	SOLUTION NMR
1KVJ	SOLUTION NMR
1Q8L	SOLUTION NMR
1S6O	SOLUTION NMR
1S6U	SOLUTION NMR
1Y3J	SOLUTION NMR
1Y3K	SOLUTION NMR
1YJR	SOLUTION NMR
1YJT	SOLUTION NMR
1YJU	SOLUTION NMR
1YJV	SOLUTION NMR
2AW0	SOLUTION NMR
2G9O	SOLUTION NMR
2GA7	SOLUTION NMR
2K1R	SOLUTION NMR
2KIJ	SOLUTION NMR
2KMV	SOLUTION NMR
2KMX	SOLUTION NMR
7LU8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04656-F1	73.59	0.11

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1044 (4-aspartylphosphate intermediate)

Ligand- & substrate-binding residues (16): 18; 19; 22; 182; 185; 288; 291; 388; 391; 499; 502; 575 …

Post-translational modifications (17): 152, 270, 327, 339, 353, 357, 362, 1212, 1430, 1432, 1460, 1463, 1466, 1469, 1473, 1476, 1486

Glycosylation sites (2): 686, 975

Mutagenesis-validated functional residues (3):

Position	Phenotype
22	impairs cu(+)-bridged heterodimer formation with atox1 while increasing the reactivity toward cisplatin.
1044	impairs tyrosinase activity involved in melanin synthesis.
1487–1488	loss of relocalization to the trans-golgi.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-6803544	Ion influx/efflux at host-pathogen interface
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-2262752	Cellular responses to stress
R-HSA-382551	Transport of small molecules
R-HSA-6803157	Antimicrobial peptides
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711123	Cellular response to chemical stress
R-HSA-983712	Ion channel transport

MSigDB gene sets: 717 (showing top): GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT

GO Biological Process (48): blood vessel development (GO:0001568), release of cytochrome c from mitochondria (GO:0001836), blood vessel remodeling (GO:0001974), regulation of oxidative phosphorylation (GO:0002082), obsolete L-tryptophan metabolic process (GO:0006568), obsolete tyrosine metabolic process (GO:0006570), catecholamine metabolic process (GO:0006584), copper ion transport (GO:0006825), intracellular copper ion homeostasis (GO:0006878), mitochondrion organization (GO:0007005), locomotory behavior (GO:0007626), glycoprotein biosynthetic process (GO:0009101), detoxification of copper ion (GO:0010273), regulation of gene expression (GO:0010468), copper ion import (GO:0015677), removal of superoxide radicals (GO:0019430), cerebellar Purkinje cell differentiation (GO:0021702), pyramidal neuron development (GO:0021860), central nervous system neuron development (GO:0021954), extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), hair follicle morphogenesis (GO:0031069), T-helper cell differentiation (GO:0042093), epinephrine metabolic process (GO:0042414), norepinephrine metabolic process (GO:0042415), dopamine metabolic process (GO:0042417), norepinephrine biosynthetic process (GO:0042421), serotonin metabolic process (GO:0042428), pigmentation (GO:0043473), negative regulation of neuron apoptotic process (GO:0043524), skin development (GO:0043588), obsolete negative regulation of catecholamine metabolic process (GO:0045914), ATP metabolic process (GO:0046034), positive regulation of melanin biosynthetic process (GO:0048023), elastic fiber assembly (GO:0048251), lung alveolus development (GO:0048286), neuron projection morphogenesis (GO:0048812), dendrite morphogenesis (GO:0048813), cartilage development (GO:0051216), neuron apoptotic process (GO:0051402)

GO Molecular Function (15): copper ion transmembrane transporter activity (GO:0005375), copper ion binding (GO:0005507), ATP binding (GO:0005524), superoxide dismutase copper chaperone activity (GO:0016532), ATP hydrolysis activity (GO:0016887), copper-dependent protein binding (GO:0032767), P-type divalent copper transporter activity (GO:0043682), P-type monovalent copper transporter activity (GO:0140581), cuprous ion binding (GO:1903136), nucleotide binding (GO:0000166), transporter activity (GO:0005215), protein binding (GO:0005515), P-type ion transporter activity (GO:0015662), ATPase-coupled monoatomic cation transmembrane transporter activity (GO:0019829), metal ion binding (GO:0046872)

GO Cellular Component (26): late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), trans-Golgi network transport vesicle (GO:0030140), axon (GO:0030424), dendrite (GO:0030425), phagocytic vesicle membrane (GO:0030670), early endosome membrane (GO:0031901), trans-Golgi network membrane (GO:0032588), melanosome membrane (GO:0033162), neuron projection (GO:0043005), neuronal cell body (GO:0043025), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), endosome (GO:0005768), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202), bounding membrane of organelle (GO:0098588)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Cellular response to chemical stress	1
Antimicrobial peptides	1
Ion channel transport	1
Immune System	1
Cellular responses to stimuli	1
Innate Immune System	1
Cellular responses to stress	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	4
central nervous system neuron differentiation	2
copper ion transmembrane transporter activity	2
P-type ion transporter activity	2
ATPase-coupled monoatomic cation transmembrane transporter activity	2
endomembrane system	2
intracellular membrane-bounded organelle	2
neuron projection	2
vasculature development	1
anatomical structure development	1
apoptotic mitochondrial changes	1
apoptotic signaling pathway	1
tissue remodeling	1
oxidative phosphorylation	1
regulation of aerobic respiration	1
biogenic amine metabolic process	1
catechol-containing compound metabolic process	1
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
copper ion homeostasis	1
organelle organization	1
behavior	1
macromolecule biosynthetic process	1
glycoprotein metabolic process	1
carbohydrate derivative biosynthetic process	1
detoxification of inorganic compound	1
stress response to copper ion	1
gene expression	1
regulation of macromolecule biosynthetic process	1
copper ion transport	1
superoxide metabolic process	1
cellular response to superoxide	1
cellular oxidant detoxification	1
cell differentiation in hindbrain	1
cerebellar Purkinje cell layer formation	1
pyramidal neuron differentiation	1
forebrain neuron development	1
neuron development	1
extracellular structure organization	1

Protein interactions and networks

STRING

3690 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP7A	EIF4G1	Q04637	989
ATP7A	ATOX1	O00244	978
ATP7A	POMC	P01189	964
ATP7A	SLC31A1	O15431	934
ATP7A	SLC31A2	O15432	905
ATP7A	CP	P00450	904
ATP7A	MC3R	P41968	896
ATP7A	MKNK1	Q9BUB5	841
ATP7A	EIF4E	P06730	827
ATP7A	H3BSS0	H3BSS0	802
ATP7A	MKNK2	Q9HBH9	796
ATP7A	EIF4G2	P78344	789
ATP7A	PDZD11	Q5EBL8	776
ATP7A	COX17	Q14061	775
ATP7A	GNE	Q9Y223	757

IntAct

77 interactions, top by confidence:

A	B	Type	Score
POLR2J	POLR1C	psi-mi:“MI:0914”(association)	0.830
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
PDZD11	ATP7A	psi-mi:“MI:0915”(physical association)	0.610
ATP7A	PDZD11	psi-mi:“MI:0915”(physical association)	0.610
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
COG6	EXOC5	psi-mi:“MI:0914”(association)	0.530
ITM2A	NDUFB5	psi-mi:“MI:0914”(association)	0.530
RAB29	CHM	psi-mi:“MI:0914”(association)	0.530
COG5	BSG	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
ATP7A	DBH	psi-mi:“MI:0914”(association)	0.500
ATP7A	DBH	psi-mi:“MI:0915”(physical association)	0.500
ATP7A	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
Dtnbp1	DBH	psi-mi:“MI:0914”(association)	0.350
	FAM171A2	psi-mi:“MI:0914”(association)	0.350
rs27_rs27l_human	POTEF	psi-mi:“MI:0914”(association)	0.350
FURIN	ESYT2	psi-mi:“MI:0914”(association)	0.350
IGHM	ESYT2	psi-mi:“MI:0914”(association)	0.350
CLEC2D	TMEM120B	psi-mi:“MI:0914”(association)	0.350

BioGRID (134): ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS), ATP7A (Proximity Label-MS), ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS), GLRX (Two-hybrid), ATP7A (Affinity Capture-Western), ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS), ATP7A (Affinity Capture-MS)

ESM2 similar proteins: A0A0P0X004, A1A4L5, A3AWA4, D3ZVK1, E1BPX4, I0IUP3, O81108, P32232, P35670, P49015, P70705, Q04656, Q07G10, Q0V9N0, Q0V9Q6, Q13057, Q2QMX9, Q37145, Q4VNC1, Q58H57, Q5F310, Q5XF90, Q64430, Q64446, Q64535, Q6GNY1, Q6H7M3, Q6PCN7, Q7X8B5, Q804S5, Q80SY4, Q80Y20, Q86YT6, Q8CGS6, Q8L5Z4, Q91WT9, Q95216, Q95K79, Q96BT7, Q9CWV1

Diamond homologs: A0A0P0X004, A0R3A7, A3AWA4, A5IVY3, A6QK47, A6U4T8, A7X6S1, A8YZ02, A8Z3F8, B2HEM2, B9DFX7, O08462, O29777, O30085, O31688, O32219, O32220, O32619, O33533, O59666, P05425, P07893, P0A503, P18398, P20021, P30336, P32113, P35670, P37279, P37385, P37617, P38360, P38995, P46839, P46840, P49015, P55989, P58341, P58342, P58414

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ATP7A	“up-regulates activity”	SOD3
AKT2	“up-regulates quantity by stabilization”	ATP7A	phosphorylation
ATP7A	“up-regulates quantity”	copper(1+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

2363 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	157
Likely pathogenic	118
Uncertain significance	923
Likely benign	833
Benign	97

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064448	NM_000052.7(ATP7A):c.1898_1911del (p.Lys633fs)	Pathogenic
1073823	NC_000023.10:g.(?77270139)(77271398_?)del	Pathogenic
1073824	NC_000023.10:g.(?77227108)(77258743_?)del	Pathogenic
11782	NM_000052.7(ATP7A):c.1910C>T (p.Ser637Leu)	Pathogenic
11783	ATP7A, 8-BP DEL, NT1552	Pathogenic
11784	NM_000052.7(ATP7A):c.2938C>T (p.Arg980Ter)	Pathogenic
11788	NM_000052.7(ATP7A):c.3056G>A (p.Gly1019Asp)	Pathogenic
11789	NM_000052.7(ATP7A):c.1947-3_1948dup	Pathogenic
11791	NG_013224.2:g.(66066_82545)_(84263_92781)del	Pathogenic
11792	NM_000052.7(ATP7A):c.3911A>G (p.Asn1304Ser)	Pathogenic
11793	NM_000052.7(ATP7A):c.601C>T (p.Arg201Ter)	Pathogenic
11795	NM_000052.7(ATP7A):c.4156C>T (p.Pro1386Ser)	Pathogenic
1351221	NM_000052.7(ATP7A):c.2186G>A (p.Trp729Ter)	Pathogenic
1356350	NC_000023.10:g.(?77264993)(77268389_?)del	Pathogenic
1365570	NC_000023.10:g.(?77243718)(77245474_?)del	Pathogenic
1403273	NM_000052.7(ATP7A):c.802C>T (p.Gln268Ter)	Pathogenic
1458814	NC_000023.10:g.(?77275721)(77279056_?)del	Pathogenic
1459436	NC_000023.10:g.(?77227108)(77227268_?)del	Pathogenic
1460210	NM_000052.7(ATP7A):c.3560G>A (p.Trp1187Ter)	Pathogenic
150780	GRCh38/hg38 Xq21.1(chrX:77995123-78039221)x0	Pathogenic
1685559	NM_000052.7(ATP7A):c.437del (p.Leu146fs)	Pathogenic
1685560	NM_000052.7(ATP7A):c.1668_1680del (p.Ile556fs)	Pathogenic
1685561	NM_000052.7(ATP7A):c.3659-1G>A	Pathogenic
1685562	NM_000052.7(ATP7A):c.3802-1G>A	Pathogenic
1708320	NM_000052.7(ATP7A):c.2406+3A>C	Pathogenic
1735008	NM_000052.7(ATP7A):c.3799C>T (p.Gln1267Ter)	Pathogenic
1736386	NM_000052.7(ATP7A):c.3946dup (p.Ile1316fs)	Pathogenic
1806151	NM_000052.7(ATP7A):c.2280C>G (p.Tyr760Ter)	Pathogenic
1976390	NM_000052.7(ATP7A):c.2446del (p.Gln816fs)	Pathogenic
2003571	NM_000052.7(ATP7A):c.466_467insC (p.Lys156fs)	Pathogenic

SpliceAI

4591 predictions. Top by Δscore:

Variant	Effect	Δscore
X:77910833:CAGGT:C	donor_loss	1.0000
X:77910834:AGG:A	donor_loss	1.0000
X:77910835:GGTA:G	donor_loss	1.0000
X:77910837:T:A	donor_loss	1.0000
X:77923053:G:GG	donor_gain	1.0000
X:77971615:TAACA:T	acceptor_loss	1.0000
X:77971616:A:AG	acceptor_gain	1.0000
X:77971616:AACAG:A	acceptor_gain	1.0000
X:77971618:CAGG:C	acceptor_loss	1.0000
X:77971619:A:AG	acceptor_gain	1.0000
X:77971619:A:T	acceptor_loss	1.0000
X:77971619:AG:A	acceptor_gain	1.0000
X:77971620:G:GT	acceptor_gain	1.0000
X:77971620:GG:G	acceptor_gain	1.0000
X:77971620:GGA:G	acceptor_gain	1.0000
X:77971620:GGAA:G	acceptor_gain	1.0000
X:77971620:GGAAT:G	acceptor_gain	1.0000
X:77971758:TAAGG:T	donor_loss	1.0000
X:77971762:G:GG	donor_gain	1.0000
X:77971762:GT:G	donor_loss	1.0000
X:77988238:AAAGG:A	acceptor_loss	1.0000
X:77988239:AAGGT:A	acceptor_loss	1.0000
X:77988240:A:AG	acceptor_loss	1.0000
X:77988732:G:C	donor_loss	1.0000
X:77988733:T:A	donor_loss	1.0000
X:77989231:A:AG	acceptor_gain	1.0000
X:77989232:G:GG	acceptor_gain	1.0000
X:78003232:TTGTT:T	donor_gain	1.0000
X:78003234:GTT:G	donor_gain	1.0000
X:78003235:TTGTA:T	donor_loss	1.0000

AlphaMissense

9824 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:78013086:G:C	G794R	1.000
X:78013090:G:C	R795P	1.000
X:78014690:T:C	L812S	1.000
X:78020373:T:C	L919P	1.000
X:78020384:G:C	A923P	1.000
X:78029331:T:C	C1000R	1.000
X:78029337:T:C	C1002R	1.000
X:78029338:G:A	C1002Y	1.000
X:78029339:T:G	C1002W	1.000
X:78029350:T:A	L1006Q	1.000
X:78029350:T:C	L1006P	1.000
X:78029353:C:A	A1007D	1.000
X:78029365:C:A	A1011D	1.000
X:78029407:T:C	L1025P	1.000
X:78031419:A:C	D1044A	1.000
X:78042629:G:C	K1282N	1.000
X:78042629:G:T	K1282N	1.000
X:78042682:G:A	G1300E	1.000
X:78042695:T:A	N1304K	1.000
X:78042695:T:G	N1304K	1.000
X:78042696:G:C	D1305H	1.000
X:78042697:A:C	D1305A	1.000
X:78042697:A:G	D1305G	1.000
X:78042697:A:T	D1305V	1.000
X:78042698:C:A	D1305E	1.000
X:78042698:C:G	D1305E	1.000
X:78042706:C:A	A1308D	1.000
X:78042709:T:C	L1309P	1.000
X:78042765:G:C	A1328P	1.000
X:78043385:T:A	N1358K	1.000

dbSNP variants (sampled 300 via entrez): RS1000007438 (X:77912576 A>G), RS1000091431 (X:77958205 C>T), RS1000100513 (X:77913084 A>G), RS1000155972 (X:77913427 A>T), RS1000168750 (X:77975547 T>G), RS1000263961 (X:77975864 A>G), RS1000290355 (X:78045132 C>T), RS1000389918 (X:78034664 A>G), RS1000461898 (X:78034988 C>A), RS1000505847 (X:77986087 A>G), RS1000572971 (X:77953061 C>T), RS1000576079 (X:78023991 T>C), RS1000634012 (X:78014056 C>G), RS1000634769 (X:77942050 A>T), RS1000665064 (X:78014276 G>A)

Disease associations

OMIM: gene MIM:300011 | disease phenotypes: MIM:300489, MIM:304150, MIM:309400, MIM:118220, MIM:604916, MIM:616580, MIM:130000, MIM:182960, MIM:301040, MIM:300853

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked distal spinal muscular atrophy type 3	Definitive	X-linked
Menkes disease	Definitive	X-linked
occipital horn syndrome	Definitive	X-linked
Hirschsprung disease	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Menkes disease	Definitive	XL
X-linked distal spinal muscular atrophy type 3	Moderate	XL

Mondo (12): X-linked distal spinal muscular atrophy type 3 (MONDO:0010338), occipital horn syndrome (MONDO:0010572), Menkes disease (MONDO:0010651), Charcot-Marie-Tooth disease (MONDO:0015626), Charcot-Marie-Tooth disease type 2 (MONDO:0018993), Au-Kline syndrome (MONDO:0014700), Ehlers-Danlos syndrome (MONDO:0020066), neuronopathy, distal hereditary motor, autosomal dominant 1 (MONDO:0008451), alpha thalassemia-X-linked intellectual disability syndrome (MONDO:0010519), X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (MONDO:0010455), intellectual disability (MONDO:0001071), Hirschsprung disease (MONDO:0018309)

Orphanet (13): X-linked distal spinal muscular atrophy type 3 (Orphanet:139557), Occipital horn syndrome (Orphanet:198), Menkes disease (Orphanet:565), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746), Okamoto syndrome (Orphanet:2729), Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome (Orphanet:453499), Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to a point mutation (Orphanet:453504), Ehlers-Danlos syndrome (Orphanet:98249), Distal hereditary motor neuropathy type 1 (Orphanet:139518), X-linked alpha-thalassemia-intellectual disability syndrome (Orphanet:847), XMEN (Orphanet:317476), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

178 total (30 of 178 shown, HPO-id order):

HPO	Term
HP:0000010	Recurrent urinary tract infections
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000126	Hydronephrosis
HP:0000174	Abnormal palate morphology
HP:0000218	High palate
HP:0000239	Large fontanelles
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000269	Prominent occiput
HP:0000270	Delayed cranial suture closure
HP:0000271	Abnormality of the face
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000293	Full cheeks
HP:0000298	Mask-like facies
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000444	Convex nasal ridge
HP:0000472	Long neck
HP:0000494	Downslanted palpebral fissures
HP:0000708	Atypical behavior
HP:0000759	Abnormal peripheral nervous system morphology
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000774	Narrow chest
HP:0000885	Broad ribs
HP:0000894	Short clavicles
HP:0000916	Broad clavicles

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008839_355	Height	3.000000e-30

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007706	Menkes Kinky Hair Syndrome	C10.228.140.163.100.540; C10.597.606.360.455.687; C16.320.322.500.687; C16.320.400.525.687; C16.320.565.189.540; C16.320.565.618.590; C17.800.329.968; C18.452.132.100.540; C18.452.648.189.540; C18.452.648.618.590
C538258	ATR-X syndrome (supp.)
C565736	Hydronephrosis, Congenital, with Cleft Palate, Characteristic Facies, Hypotonia, and Mental Retardation (supp.)
C566675	Neuronopathy, Distal Hereditary Motor, Type I (supp.)
C537860	Occipital horn syndrome (supp.)
C564506	Spinal Muscular Atrophy, Distal, X-Linked 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291564 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2227291	Toxicity	3	docetaxel;thalidomide	Prostatic Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2227291	ATP7A	3	2.00	1	docetaxel;thalidomide

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — P1B P-type ATPases: Cu⁺-ATPases

CTD chemical–gene interactions

70 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Copper	affects transport, decreases response to substance, increases activity, affects cotreatment, increases expression (+17 more)	24
Cisplatin	increases response to substance, affects response to substance, decreases reaction, increases uptake, decreases response to substance (+5 more)	8
cupric chloride	increases reaction, decreases glutathionylation, decreases response to substance, increases abundance, decreases uptake (+4 more)	5
Oxaliplatin	increases expression, affects response to substance, decreases response to substance, decreases expression, increases response to substance	4
bathocuproine sulfonate	affects binding, affects cotreatment, increases reaction, decreases reaction, increases activity	2
entinostat	decreases expression, affects cotreatment	2
Hydrogen Peroxide	increases chemical synthesis, increases reaction, affects binding	2
Paraquat	increases reaction, increases response to substance, increases expression, increases chemical synthesis	2
Silver	affects binding	2
Tretinoin	increases expression	2
Valproic Acid	increases expression, increases methylation	2
Carboplatin	decreases expression, increases response to substance, decreases response to substance, increases reaction, affects localization	2
Paclitaxel	decreases response to substance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
trichostatin A	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
pyrrolidine dithiocarbamic acid	decreases expression	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
cupric oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5225762	Binding	Inhibition of MNK in human LNCaP C4-2B cells assessed as inhibition of eIF4E phosphorylation at 5 uM incubated for 2 hrs by Western blot analysis	Using Imidazo[2,1-b][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors. — ACS Med Chem Lett

Cellosaurus cell lines

21 cell lines: 12 finite cell line, 9 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1L33	GM13667	Finite cell line	Male
CVCL_1L34	GM13668	Finite cell line	Male
CVCL_1L35	GM13669	Finite cell line	Male
CVCL_1L36	GM13670	Finite cell line	Male
CVCL_1L37	GM13671	Finite cell line	Male
CVCL_1L38	GM13674	Finite cell line	Male
CVCL_1L39	GM13675	Finite cell line	Male
CVCL_7534	GM13672	Finite cell line	Male
CVCL_A8QS	Me32A-DmATP7	Finite cell line	Sex unspecified
CVCL_D8ZS	Ubigene HEK293 ATP7A KO	Transformed cell line	Female

Clinical trials (associated diseases)

312 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00811785	PHASE3	COMPLETED	Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00001262	PHASE1/PHASE2	COMPLETED	Copper Histidine Therapy for Menkes Diseases
NCT04977388	PHASE1/PHASE2	COMPLETED	NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Occipital Horn Syndrome
NCT07398508	PHASE1/PHASE2	RECRUITING	Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Pediatric Survivors of Menkes Disease.
NCT05507996	EARLY_PHASE1	TERMINATED	Recombinant Adeno-associated Virus Administration for Patients With Menkes Syndrome
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04074512	Not specified	APPROVED_FOR_MARKETING	Copper Histidinate Treatment for Menkes Disease