CP

Summary

CP (ceruloplasmin, HGNC:2295) is a protein-coding gene on chromosome 3q24-q25.1, encoding Ceruloplasmin (P00450). Multifunctional blue, copper-binding (6-7 atoms per molecule) glycoprotein.

The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene.

Source: NCBI Gene 1356 — RefSeq curated summary.

At a glance

• Gene–disease (curated): aceruloplasminemia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,160 total — 89 pathogenic, 53 likely-pathogenic
• Phenotypes (HPO): 48
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000096

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2295
Approved symbol	CP
Name	ceruloplasmin
Location	3q24-q25.1
Locus type	gene with protein product
Status	Approved
Aliases	AB073614
Ensembl gene	ENSG00000047457
Ensembl biotype	protein_coding
OMIM	117700
Entrez	1356

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 9 protein_coding, 9 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000264613, ENST00000455472, ENST00000460674, ENST00000462336, ENST00000463556, ENST00000471356, ENST00000473296, ENST00000474204, ENST00000479771, ENST00000481169, ENST00000489736, ENST00000490639, ENST00000494544, ENST00000497797, ENST00000497902, ENST00000870686, ENST00000870687, ENST00000870688, ENST00000870689, ENST00000870690

RefSeq mRNA: 1 — MANE Select: NM_000096 NM_000096

CCDS: CCDS3141

Canonical transcript exons

ENST00000264613 — 19 exons

Exon	Start	End
ENSE00001008197	149221647	149221829
ENSE00001245656	149176250	149176412
ENSE00003463270	149177840	149177979
ENSE00003463548	149179556	149179662
ENSE00003467839	149202102	149202241
ENSE00003470933	149198367	149198578
ENSE00003486135	149172497	149173730
ENSE00003508771	149212451	149212698
ENSE00003530045	149182005	149182133
ENSE00003567271	149210167	149210379
ENSE00003573642	149209211	149209384
ENSE00003585505	149199712	149199864
ENSE00003594625	149186520	149186732
ENSE00003635687	149188052	149188202
ENSE00003639931	149206168	149206339
ENSE00003646391	149207363	149207617
ENSE00003657393	149178415	149178631
ENSE00003667758	149185239	149185446
ENSE00003692951	149183466	149183605

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 99.68.

FANTOM5 (CAGE): breadth broad, TPM avg 8.0396 / max 2023.4974, expressed in 333 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45003	7.0473	285
45005	0.5511	97
45004	0.3220	103
44999	0.0778	23
45006	0.0331	14
45001	0.0083	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.68	gold quality
liver	UBERON:0002107	99.34	gold quality
palpebral conjunctiva	UBERON:0001812	99.12	gold quality
nasal cavity epithelium	UBERON:0005384	98.72	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.59	gold quality
bronchial epithelial cell	CL:0002328	98.12	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.68	gold quality
nasal cavity mucosa	UBERON:0001826	97.59	gold quality
epithelium of bronchus	UBERON:0002031	97.35	gold quality
bronchus	UBERON:0002185	97.15	gold quality
choroid plexus epithelium	UBERON:0003911	96.24	gold quality
ascending aorta	UBERON:0001496	95.06	gold quality
right coronary artery	UBERON:0001625	95.00	gold quality
thoracic aorta	UBERON:0001515	94.79	gold quality
aorta	UBERON:0000947	94.21	gold quality
tibial artery	UBERON:0007610	94.03	gold quality
popliteal artery	UBERON:0002250	94.01	gold quality
minor salivary gland	UBERON:0001830	93.86	gold quality
calcaneal tendon	UBERON:0003701	93.14	gold quality
colonic epithelium	UBERON:0000397	93.07	gold quality
descending thoracic aorta	UBERON:0002345	92.54	gold quality
rectum	UBERON:0001052	91.12	gold quality
right atrium auricular region	UBERON:0006631	91.00	gold quality
spleen	UBERON:0002106	90.26	gold quality
tendon	UBERON:0000043	90.13	gold quality
epithelium of nasopharynx	UBERON:0001951	89.98	gold quality
mouth mucosa	UBERON:0003729	89.58	gold quality
lymph node	UBERON:0000029	89.16	gold quality
trachea	UBERON:0003126	89.16	gold quality
left coronary artery	UBERON:0001626	88.92	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	4924.01
E-GEOD-98556	yes	4573.19
E-GEOD-130148	yes	3779.17
E-HCAD-23	yes	3713.30
E-MTAB-7316	yes	2137.74
E-MTAB-11121	yes	2108.84
E-GEOD-137537	yes	1761.27
E-HCAD-24	yes	1382.54
E-MTAB-10553	yes	738.12
E-MTAB-8142	yes	97.69
E-HCAD-9	yes	54.74
E-CURD-114	yes	50.14
E-MTAB-10287	yes	43.48
E-HCAD-4	yes	23.63
E-MTAB-7249	yes	11.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPZ, EGR1, FOXC2, FOXO1, GLI1, GLI3, HIF1A, JUN, MBD2, RNF2, SP1, SSRP1

miRNA regulators (miRDB)

77 targeting CP, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-4729	99.69	72.18	4233

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• CERULOPLASMIN haS a role in iron uptake rather than release in BT325 cells. (PMID:11681312)
• difference in the molecular structure between human and bovine ceruloplasmin using SDS-PAGE and MALDI-TOF mass spectrometry (PMID:11689010)
• gene coding and flanking regions were sequenced and examined for mutations that might modulate the iron burden of individuals harboring the common mutant hemochromatosis HFE genotype or cause hemochromatosis independent of mutations in the HFE gene (PMID:11783942)
• Studies of the ceruloplasmin-lactoferrin complex (PMID:11908641)
• results show that insulin functions as a bidirectional, condition-dependent regulator of hepatic cell Cp expression; the unique regulation of Cp may reflect its dual roles in inflammation and iron homeostasis (PMID:12029093)
• Carnosine, homocarnosine and anserine significantly inhibited the aggregation of CP induced by peroxyl radicals. (PMID:12132593)
• Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), ceruloplasmin (Cp), and transferrin (Tf) in rheumatoid arthritis. Serum Tf levels were significantly diminished and serum levels of sICAM-1 and Cp were significantly increased. (PMID:12175089)
• the three-copper cluster at the N-terminal-C-terminal interface plays a crucial role in the structural stability of human ceruloplasmin (PMID:12177070)
• elucidation of mechanisms of copper incorporation (PMID:12351628)
• Determination of specific antioxidants like ceruloplasmin in serum may be of value in the early diagnosis of prostate and colon cancer. (PMID:12708132)
• data show that ceruloplasmin stimulates iron release from macrophages under hypoxic conditions by a ferroxidase-dependent mechanism (PMID:12952974)
• Haptoglobin polymorphism was correlated with ceruloplasmin ferroxidase activity in a sample population of unrelated black Jordanians and activity is both haptoglobin type and concentration dependent. (PMID:15103512)
• Urinary levels are increaed in normoalbuminuric type 2 diabetic patients. (PMID:15111541)
• 5 new missense (I63T, P477L, T551I, R793H, T841R) & 3 new silent variations (g:9230/C->A, g:42221/C->T, g:4400/T->C) were found. Cp colocalized with Fe in Lewy bodies, suggesting a role in pathogenesis of Parkinson disease. (PMID:15557511)
• REVIEW: mechanism for the involvement of ceruloplasmin in cardiovascular disease (PMID:15668644)
• hypoxia-inducible factor (HIF)-1 has a role in ceruloplasmin regulation (PMID:15741220)
• Cp polypeptides with molecular weight of nearly 30 kDa were found in mitochondria of HuTu 80 cells (PMID:15752613)
• altered activity of ceruloplasmin may present a vulnerability factor for iron induced oxidative stress in Parkinson’s disease (PMID:16150804)
• Increased levels in urine predicts development of microalbuminuria in type 2 diabetes. (PMID:16373913)
• results showed that exposure of CP to methylglyoxal led to protein aggregation and that aggregation of CP induced the inactivation of feroxidase and the release of copper ions (PMID:16756764)
• Results describe the biochemical features of wild-type and mutant GPI-anchored ceruloplasmin. (PMID:16775387)
• A biochemical analysis of the patients’ serum and a biogenesis study of G969S mutant ceruloplasmin using mammalian cell culture system resulted in the synthesis and secretion of only apoceruloplasmin without any ferroxidase activity. (PMID:16831606)
• In a Chinese woman who had diabetes mellitus, undetectable ceruloplasmin, hand tremor, neck dystonia, and cognitive disturbances, genetic analyses revealed a novel homozygous mutation (848G > C or W283S) in exon 5 in the ceruloplasmin gene. (PMID:17013908)
• ceruloplasmin gene is regulated by activator protein-1 site in the gene by redox active copper. (PMID:17032174)
• CP levels wefre determined in children with Henoch-Schonlein purpura. (PMID:17404760)
• describe a study of the conformation of the human lactoferrin/ceruloplasmin complex in solution using small angle X-ray scattering (PMID:17597152)
• The truncated mutant containing Cys-881 was able to pass through the ER and was secreted, while the truncated mutant protein without Cys-881 appeared to accumulate in the ER thus leading to ER stress and eventually resulting in cell death. (PMID:17637479)
• In vitro equilibrium unfolding of CP involves intermediates and the copper ions are removed in stages. (PMID:17661447)
• With regard to septic liver dysfunction, signs of cholestasis were mostly reflected in greater increases in Cp (PMID:17688883)
• In contrast, apo-CP unfolds rapidly: the denatured state is reached in <2 days at 37 degrees C. (PMID:17965133)
• The involvement of lymphocyte-derived CP on host defense processes via its anti/prooxidant properties is proposed, giving further support for a close functional interaction between the immune system and the Fe metabolism. (PMID:17991445)
• stable complex between these Cp and Hp and Tf does not occur under the experimental conditions used (PMID:18022819)
• In the cerebrospinal fluid of Alzheimer’s disease patients the decrease of active CP, associated with the increase in the pool of copper not sequestered by this protein, may play a role in the neurodegenerative process (PMID:18060472)
• Measurement of Cp separated by the present method could be useful for the diagnosis of ITP in the presence of thrombocytopenia and a non- or low-inflammatory state (PMID:18187043)
• We report two siblings with markedly different phenotypes carrying a novel mutation: a homozygous deletion of two nucleotides (1257-1258 TT del) causing the premature stop of the Cp protein translation (Y401X). (PMID:18200628)
• Multiple motor system dysfunction associated with a heterozygous ceruloplasmin gene mutation. (PMID:18293024)
• Results describe the activity of ferroxidase, SOD1, and cofactors in CSF of patients with Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, or amyotrophic lateral sclerosis. (PMID:18307039)
• Investigated of brain iron levels in two asymptomatic young adult carriers with heterozygous mutations of Cp gene by using T2*-weighted MR images. (PMID:18311828)
• Ceruloplasmin is a better predictor of the long-term prognosis compared with fibrinogen, CRP, and IL-6 in patients with severe unstable angina. (PMID:18388036)
• there is an increase in ceruloplasmin levels in placental tissue in preeclampsia compared to preterm and normal controls (PMID:18679377)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cp	ENSDARG00000010312
mus_musculus	Cp	ENSMUSG00000003617
rattus_norvegicus	Cp	ENSRNOG00000011913

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Ceruloplasmin — P00450 (reviewed: P00450)

Alternative names: Cuproxidase ceruloplasmin, Ferroxidase ceruloplasmin, Glutathione peroxidase ceruloplasmin, Glutathione-dependent peroxiredoxin ceruloplasmin

All UniProt accessions (5): P00450, D6RE86, E9PFZ2, H7C5N5, H7C5R1

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional blue, copper-binding (6-7 atoms per molecule) glycoprotein. It has ferroxidase activity oxidizing Fe(2+) to Fe(3+) without releasing radical oxygen species. It is involved in iron transport across the cell membrane. Copper ions provide a large number of enzymatic activites. Oxidizes highly toxic ferrous ions to the ferric state for further incorporation onto apo-transferrins, catalyzes Cu(+) oxidation and promotes the oxidation of biogenic amines such as norepinephrin and serotonin. Provides Cu(2+) ions for the ascorbate-mediated deaminase degradation of the heparan sulfate chains of GPC1. Has glutathione peroxidase-like activity, can remove both hydrogen peroxide and lipid hydroperoxide in the presence of thiols. Also shows NO-oxidase and NO2 synthase activities that determine endocrine NO homeostasis.

Subunit / interactions. Found in a complex with MPO and LTF; interacts directly with MPO and LTF, which allows Fe(3+) incorporation into LTF, activation of CP ferroxidase activity and protection of CP antioxidant properties by MPO.

Subcellular location. Secreted.

Tissue specificity. Expressed by the liver and secreted in plasma.

Disease relevance. Aceruloplasminemia (ACEP) [MIM:604290] An autosomal recessive disorder of iron metabolism characterized by iron accumulation in the brain as well as visceral organs. Clinical features consist of the triad of retinal degeneration, diabetes mellitus and neurological disturbances. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 6 Cu(2+) cations per monomer.

Similarity. Belongs to the multicopper oxidase family.

RefSeq proteins (1): NP_000087* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001117	Cu-oxidase_2nd	Domain
IPR002355	Cu_oxidase_Cu_BS	Binding_site
IPR008972	Cupredoxin	Homologous_superfamily
IPR011706	Cu-oxidase_C	Domain
IPR011707	Cu-oxidase-like_N	Domain
IPR033138	Cu_oxidase_CS	Conserved_site
IPR045087	Cu-oxidase_fam	Family
IPR048236	Ceruloplasmin-like_CuRO_5	Domain

Pfam: PF00394, PF07731, PF07732

Enzyme classification (BRENDA):

• EC 1.16.3.1 — ferroxidase (BRENDA: 52 organisms, 108 substrates, 62 inhibitors, 161 Km, 41 kcat entries)

Substrate kinetics (BRENDA)

54 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FE2+	0.0006–14.1	29
HYDROQUINONE	0.018–30.5	22
P-PHENYLENEDIAMINE	0.005–1.19	18
FE(II)	0.0006–3.994	14
O2	0.0011–0.0632	10
O-DIANISIDINE	0.12–0.76	5
NADH	0.14–0.23	4
N,N’-DIMETHYL-P-PHENYLENEDIAMINE	0.06–0.164	3
L-EPINEPHRINE	0.0026–5.8	2
O-PHENYLENEDIAMINE	0.0029–4.15	2
2-CHLORO-P-PHENYLENEDIAMINE	0.241	1
2-METHOXY-P-PHENYLENEDIAMINE	0.161	1
2-METHYL-P-PHENYLENEDIAMINE	0.213	1
2-NITRO-P-PHENYLENEDIAMINE	0.0013	1
2-SULFONIC ACID-P-PHENYLENEDIAMINE	0.0026	1

Catalyzed reactions (Rhea), 5 shown:

• 4 Fe(2+) + O2 + 4 H(+) = 4 Fe(3+) + 2 H2O (RHEA:11148)
• 2 glutathione + H2O2 = glutathione disulfide + 2 H2O (RHEA:16833)
• 4 Cu(+) + O2 + 4 H(+) = 4 Cu(2+) + 2 H2O (RHEA:30083)
• a hydroperoxide + 2 glutathione = an alcohol + glutathione disulfide + H2O (RHEA:62632)
• 4 nitric oxide + O2 + 2 H2O = 4 nitrite + 4 H(+) (RHEA:78539)

UniProt features (172 total): strand 67, binding site 40, helix 30, sequence variant 7, turn 6, domain 6, glycosylation site 6, disulfide bond 5, signal peptide 1, chain 1, modified residue 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4ENZ	X-RAY DIFFRACTION	2.6
2J5W	X-RAY DIFFRACTION	2.8
1KCW	X-RAY DIFFRACTION	3
4EJX	X-RAY DIFFRACTION	4.69

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00450-F1	93.79	0.90

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): 699 (nucleophile; for glutathione peroxidase activity)

Ligand- & substrate-binding residues (40): 64; 67; 120 (type 2 copper site); 120; 122 (type 3 copper site); 128; 143; 146; 147; 180 (type 3 copper site); 180; 182 (type 3 copper site) …

Post-translational modifications (1): 722

Disulfide bonds (5): 174–200, 276–357, 534–560, 637–718, 874–900

Glycosylation sites (6): 138, 358, 397, 588, 762, 926

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-425410	Metal ion SLC transporters
R-HSA-5619049	Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)
R-HSA-5619060	Defective CP causes aceruloplasminemia (ACERULOP)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-917937	Iron uptake and transport

MSigDB gene sets: 372 (showing top): MODULE_93, HNF3ALPHA_Q6, HARRIS_HYPOXIA, GOCC_VACUOLAR_MEMBRANE, MODULE_418, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN

GO Biological Process (4): intracellular copper ion homeostasis (GO:0006878), intracellular iron ion homeostasis (GO:0006879), negative regulation of translation (GO:0017148), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (9): ferroxidase activity (GO:0004322), glutathione peroxidase activity (GO:0004602), copper ion binding (GO:0005507), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on metal ions, oxygen as acceptor (GO:0016724), phospholipid-hydroperoxide glutathione peroxidase activity (GO:0047066), protein-folding chaperone binding (GO:0051087), oxidoreductase activity, acting on metal ions (GO:0016722), metal ion binding (GO:0046872)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), lysosomal membrane (GO:0005765), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
SLC transporter disorders	2
Metabolism of proteins	1
SLC-mediated transmembrane transport	1
Post-translational protein modification	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular monoatomic cation homeostasis	2
peroxidase activity	2
cellular anatomical structure	2
copper ion homeostasis	1
inorganic ion homeostasis	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
cellular detoxification	1
oxidoreductase activity, acting on metal ions, oxygen as acceptor	1
transition metal ion binding	1
catalytic activity	1
oxidoreductase activity, acting on metal ions	1
protein binding	1
oxidoreductase activity	1
cation binding	1
lysosome	1
lytic vacuole membrane	1
endoplasmic reticulum	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

2540 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CP	ATP7B	P35670	968
CP	LTF	P02788	957
CP	ALB	P02768	932
CP	HP	P00737	923
CP	SERPINA1	P01009	923
CP	ATP7A	Q04656	904
CP	ORM2	P19652	898
CP	ORM1	P02763	896
CP	A2M	P01023	880
CP	MRPL13	Q9BYD1	865
CP	HPX	P02790	818
CP	TTR	P02766	817
CP	H3BSS0	H3BSS0	780
CP	EPRS1	P07814	768
CP	SLC40A1	Q9NP59	763

IntAct

54 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
DDX31	IGLL5	psi-mi:“MI:0914”(association)	0.530
	CP	psi-mi:“MI:0407”(direct interaction)	0.440
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
SLC40A1	CP	psi-mi:“MI:0915”(physical association)	0.400
BTRC	CP	psi-mi:“MI:0915”(physical association)	0.370
APOA1	CNMD	psi-mi:“MI:0914”(association)	0.350
IGHG1	PDPK1	psi-mi:“MI:0914”(association)	0.350
MAPT	LANCL1	psi-mi:“MI:0914”(association)	0.350
MAPT	NCAN	psi-mi:“MI:0914”(association)	0.350
SNX27	IGLL5	psi-mi:“MI:0914”(association)	0.350
GDPD1	CP	psi-mi:“MI:0914”(association)	0.350
PEBP1	PRPSAP2	psi-mi:“MI:0914”(association)	0.350
NSD2	PFKFB2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	A2ML1	psi-mi:“MI:0914”(association)	0.350
GJB5	IGLL5	psi-mi:“MI:0914”(association)	0.350
ELOA2	XRCC2	psi-mi:“MI:0914”(association)	0.350

BioGRID (67): CP (Affinity Capture-MS), CP (Affinity Capture-MS), CP (Affinity Capture-MS), CP (Affinity Capture-MS), CP (Affinity Capture-MS), CP (Affinity Capture-MS), CP (Proximity Label-MS), CP (Affinity Capture-MS), CP (Proximity Label-MS), CP (Proximity Label-MS), CP (Affinity Capture-MS), CP (Reconstituted Complex), CP (Affinity Capture-MS), CP (Affinity Capture-MS), SERPINA3 (Affinity Capture-MS)

ESM2 similar proteins: A2Y9C2, A2Y9C5, A2ZNT5, B3EWZ9, P00450, P13635, P29162, P33434, P33436, P56193, P83388, Q00624, Q02075, Q02079, Q06K61, Q08CS6, Q0IQU1, Q0JHP8, Q2QZ80, Q2R0L0, Q2R0L2, Q2VQV9, Q3V1H3, Q4PIF8, Q4WQY8, Q58L90, Q58L91, Q593B6, Q61147, Q6MZM0, Q7SZN0, Q84J37, Q8VXX5, Q8VZA1, Q90611, Q920H8, Q966W3, Q96WT3, Q9AWU4, Q9BQS7

Diamond homologs: B3EWZ9, O18806, O88783, P00450, P00451, P12259, P12263, P13635, Q06194, Q28107, Q3V1H3, Q55P57, Q58L90, Q58L91, Q593B6, Q61147, Q6MZM0, Q7SZN0, Q920H8, Q9BQS7, Q9GLP1, Q9XT27, Q9Z0Z4, A0A0B4F1I0, A0A0B4F5S2, A0A0B4GLB5, A0A1S7IUL2, A0A2G5I8N8, A0A4Y6F0M8, A0A5B8YWJ2, E9E686, E9F648, E9RBR0, I6WZK7, Q02079, Q1PDH6, Q2QZ80, Q5ZCW1, Q69L99, Q6Z8L2

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
SHH	down-regulates	CP	binding
CP	down-regulates	SMO	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1160 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	89
Likely pathogenic	53
Uncertain significance	441
Likely benign	352
Benign	105

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070217	NM_032383.5(HPS3):c.2399dup (p.Lys801fs)	Pathogenic
1070975	NM_000096.4(CP):c.1317_1318del (p.Gly440fs)	Pathogenic
1071143	NM_000096.4(CP):c.376_379del (p.Tyr126fs)	Pathogenic
1322157	NM_000096.4(CP):c.2879-2A>G	Pathogenic
1379970	NM_000096.4(CP):c.2322C>A (p.Tyr774Ter)	Pathogenic
1416732	NM_032383.5(HPS3):c.2609C>A (p.Ser870Ter)	Pathogenic
1449523	NM_032383.5(HPS3):c.2736dup (p.Glu913fs)	Pathogenic
1451371	NM_032383.5(HPS3):c.2633del (p.Pro878fs)	Pathogenic
1451712	NM_000096.4(CP):c.1731del (p.Glu577fs)	Pathogenic
1453045	NM_000096.4(CP):c.1149G>A (p.Trp383Ter)	Pathogenic
17559	NM_000096.4(CP):c.3019-1G>A	Pathogenic
17560	NM_000096.4(CP):c.2389del (p.Glu797fs)	Pathogenic
17561	NM_000096.4(CP):c.1282_1286dup (p.Asp430fs)	Pathogenic
17562	NM_000096.4(CP):c.2630G>A (p.Trp877Ter)	Pathogenic
17563	NM_000096.4(CP):c.606dup (p.Asp203fs)	Pathogenic
1983298	NM_000096.4(CP):c.1843C>T (p.Gln615Ter)	Pathogenic
2110333	NM_032383.5(HPS3):c.2578del (p.Ser860fs)	Pathogenic
2203453	NM_000096.4(CP):c.1306C>T (p.Arg436Ter)	Pathogenic
2427031	NC_000003.11:g.(?148876443)(148885037_?)del	Pathogenic
2630109	NM_000096.4(CP):c.1991_1992del (p.Thr664fs)	Pathogenic
2708657	NM_032383.5(HPS3):c.2411C>G (p.Ser804Ter)	Pathogenic
2789971	NM_032383.5(HPS3):c.2433dup (p.Lys812Ter)	Pathogenic
2817354	NM_032383.5(HPS3):c.2706del (p.Glu903fs)	Pathogenic
2824672	NM_032383.5(HPS3):c.2546_2549del (p.Asp848_Ser849insTer)	Pathogenic
2847076	NM_032383.5(HPS3):c.2735T>A (p.Leu912Ter)	Pathogenic
2862930	NM_000096.4(CP):c.1106del (p.Lys369fs)	Pathogenic
2909769	NM_000096.4(CP):c.2149C>T (p.Gln717Ter)	Pathogenic
2918511	NM_000096.4(CP):c.2520_2523del (p.Thr841fs)	Pathogenic
3020469	NM_000096.4(CP):c.2712del (p.Tyr904_Leu905insTer)	Pathogenic
3061972	NM_000096.4(CP):c.1864+5G>A	Pathogenic

SpliceAI

3874 predictions. Top by Δscore:

Variant	Effect	Δscore
3:149163198:T:TG	donor_gain	1.0000
3:149163205:GAACA:G	donor_gain	1.0000
3:149163243:G:GT	donor_gain	1.0000
3:149163249:G:GT	donor_gain	1.0000
3:149163250:A:T	donor_gain	1.0000
3:149163261:G:GT	donor_gain	1.0000
3:149163271:G:GT	donor_gain	1.0000
3:149163841:GATAA:G	acceptor_gain	1.0000
3:149163879:G:A	acceptor_gain	1.0000
3:149163950:GT:G	donor_loss	1.0000
3:149163951:T:A	donor_loss	1.0000
3:149164248:A:T	donor_gain	1.0000
3:149167032:A:AG	acceptor_gain	1.0000
3:149167033:G:GG	acceptor_gain	1.0000
3:149167083:T:A	acceptor_gain	1.0000
3:149167884:CTAAG:C	acceptor_loss	1.0000
3:149167885:TAAG:T	acceptor_loss	1.0000
3:149167886:A:AG	acceptor_gain	1.0000
3:149167886:AAGA:A	acceptor_loss	1.0000
3:149167887:A:AG	acceptor_gain	1.0000
3:149167887:AGATA:A	acceptor_loss	1.0000
3:149167888:G:GG	acceptor_gain	1.0000
3:149167888:G:T	acceptor_loss	1.0000
3:149167888:GATA:G	acceptor_gain	1.0000
3:149167979:AAAAG:A	donor_loss	1.0000
3:149167984:G:GA	donor_loss	1.0000
3:149167985:T:A	donor_loss	1.0000
3:149177834:TCTTA:T	donor_loss	1.0000
3:149177835:CTTA:C	donor_loss	1.0000
3:149177836:TTACC:T	donor_loss	1.0000

AlphaMissense

7090 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:149207552:A:G	W283R	0.998
3:149207552:A:T	W283R	0.998
3:149207610:A:C	N263K	0.996
3:149207610:A:T	N263K	0.996
3:149209305:G:C	S229R	0.996
3:149209305:G:T	S229R	0.996
3:149209307:T:G	S229R	0.996
3:149210232:G:A	S181F	0.995
3:149176311:G:C	C1040W	0.994
3:149198525:A:G	W519R	0.994
3:149198525:A:T	W519R	0.994
3:149210212:C:G	D188H	0.993
3:149210239:A:C	Y179D	0.993
3:149176313:A:G	C1040R	0.992
3:149177914:A:G	W982R	0.992
3:149177914:A:T	W982R	0.992
3:149186667:A:G	W644R	0.992
3:149186667:A:T	W644R	0.992
3:149210190:C:T	G195E	0.992
3:149210196:A:G	L193P	0.992
3:149185429:A:G	C699R	0.991
3:149207392:A:G	L336P	0.991
3:149210191:C:G	G195R	0.991
3:149210191:C:T	G195R	0.991
3:149212512:G:C	N111K	0.991
3:149212512:G:T	N111K	0.991
3:149212565:C:G	G94R	0.991
3:149178511:A:G	S928P	0.990
3:149186725:A:C	N624K	0.990
3:149186725:A:T	N624K	0.990

dbSNP variants (sampled 300 via entrez): RS1000021821 (3:149179422 A>T), RS1000187403 (3:149172828 C>T), RS1000248652 (3:149165973 A>G), RS1000259057 (3:149209796 A>G), RS1000272426 (3:149203150 G>A), RS1000352657 (3:149215278 G>A), RS1000362201 (3:149170899 G>A), RS1000363830 (3:149166249 G>T), RS1000379729 (3:149204454 G>C), RS1000459864 (3:149192737 A>C,G), RS1000478093 (3:149171138 C>T), RS1000502540 (3:149218476 C>T), RS1000527508 (3:149218907 C>T), RS1000575892 (3:149174266 G>A), RS1000581221 (3:149167502 C>A,G,T)

Disease associations

OMIM: gene MIM:117700 | disease phenotypes: MIM:604290, MIM:614072, MIM:203300, MIM:234200

GenCC curated gene-disease

Disease	Classification	Inheritance
aceruloplasminemia	Definitive	Autosomal recessive
disorder of iron metabolism and transport	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
aceruloplasminemia	Definitive	AR

Mondo (5): aceruloplasminemia (MONDO:0011426), Hermansky-Pudlak syndrome 3 (MONDO:0013555), Hermansky-Pudlak syndrome (MONDO:0019312), neurodegeneration with brain iron accumulation (MONDO:0018307), disorder of iron metabolism and transport (MONDO:0017763)

Orphanet (4): Aceruloplasminemia (Orphanet:48818), Hermansky-Pudlak syndrome due to BLOC-2 deficiency (Orphanet:231512), Hermansky-Pudlak syndrome (Orphanet:79430), Neurodegeneration with brain iron accumulation (Orphanet:385)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000273	Facial grimacing
HP:0000473	Torticollis
HP:0000546	Retinal degeneration
HP:0000608	Macular degeneration
HP:0000639	Nystagmus
HP:0000643	Blepharospasm
HP:0000707	Abnormality of the nervous system
HP:0000726	Dementia
HP:0000741	Apathy
HP:0000819	Diabetes mellitus
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001635	Congestive heart failure
HP:0001903	Anemia
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002072	Chorea
HP:0002168	Scanning speech
HP:0002304	Akinesia
HP:0002354	Memory impairment
HP:0002396	Cogwheel rigidity
HP:0003281	Increased circulating ferritin concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001521_15	Subcutaneous adipose tissue	1.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D022861	Hermanski-Pudlak Syndrome	C11.270.040.545.400; C15.378.100.100.515; C15.378.100.685.400; C15.378.140.735.400; C15.378.463.735.400; C16.320.099.515; C16.320.290.040.100.400; C16.320.565.100.102.100.400; C16.320.850.080.100.400; C17.800.621.440.102.100.400; C17.800.827.080.100.400; C18.452.648.100.102.100.400
C538421	Neurodegeneration with brain iron accumulation (NBIA) (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Copper	decreases expression, increases activity, increases expression, increases reaction, affects binding (+1 more)	9
Iron	affects reaction, increases activity, decreases export, affects binding, increases oxidation (+1 more)	5
Lead	affects binding, affects expression, decreases activity, increases expression	4
Oxygen	affects reaction, increases activity, increases expression	4
Benzo(a)pyrene	affects cotreatment, affects expression, increases expression, increases methylation	3
Calcitriol	increases expression	3
Tretinoin	increases expression	3
bisphenol A	affects expression, decreases expression, increases methylation	2
sodium arsenite	decreases expression, increases expression	2
Zoledronic Acid	increases expression	2
Acetaminophen	decreases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Hydrogen Peroxide	decreases secretion, increases degradation, decreases expression	2
Smoke	decreases expression, decreases nitrosation	2
Tobacco Smoke Pollution	decreases expression, increases expression, affects expression	2
Valproic Acid	decreases expression	2
Cyclosporine	decreases expression	2
Copper Sulfate	affects cotreatment, increases expression, decreases expression	2
dicrotophos	decreases expression	1
bathocuproine	affects binding, decreases reaction, increases reaction	1
chloroacetaldehyde	decreases expression	1
propionaldehyde	decreases expression	1
chlortoluron	decreases expression	1
fluoranthene	affects cotreatment, affects expression	1
potassium persulfate	increases expression	1
zinc chloride	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
tetrathiomolybdate	decreases secretion	1
pyrrolidine dithiocarbamic acid	increases expression, increases reaction, increases secretion, affects binding, decreases reaction (+1 more)	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C1XX	IBMS-iPSC-077-01	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT04193592	PHASE2	UNKNOWN	Efficacy and Safety of Pirfenidone Treatment in HPS-ILD
NCT05157802	PHASE1	ACTIVE_NOT_RECRUITING	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT01104649	PHASE2/PHASE3	COMPLETED	Efficacy of Riluzole in Hereditary Cerebellar Ataxia
NCT01649687	PHASE1/PHASE2	COMPLETED	Treatment of Cerebellar Ataxia With Mesenchymal Stem Cells
NCT01958177	PHASE1/PHASE2	UNKNOWN	Clinical Study to Evaluate the Safety and Efficacy BMMNC in Cerebellar Ataxia
NCT04184453	EARLY_PHASE1	UNKNOWN	Clinical Curative Effect Evaluation Study of Treatment of Oral Deferiprone Tablets in Aceruloplasminaemia Patients
NCT00006492	Not specified	COMPLETED	Gluten-Free Diet in Patients With Gluten Sensitivity and Cerebellar Ataxia
NCT01307176	Not specified	COMPLETED	Exercise Training Program for Cerebellar Ataxia
NCT02887703	Not specified	COMPLETED	Augmenting Balance in Individuals With Cerebellar Ataxias
NCT02900508	Not specified	COMPLETED	Virtual Reality-based Training in Cerebellar Ataxia
NCT02903290	Not specified	COMPLETED	Longitudinal Monitoring of Energy Expenditure, Dynamic Stability and Fatigue During Gait in Patients With Cerebellar Ataxia Gene
NCT03120013	Not specified	COMPLETED	Rehabilitative Trial With Cerebello-Spinal tDCS in Neurodegenerative Ataxia
NCT03213106	Not specified	UNKNOWN	Cerebellar Non-invasive Stimulation in Ataxias
NCT03269201	Not specified	UNKNOWN	Brain Network Activation in Patients With Movement Disorders
NCT03341416	Not specified	UNKNOWN	Effects of Deep Brain Stimulation of the Dentate Nucleus on Cerebellar Ataxia
NCT03879018	Not specified	RECRUITING	Retraining Reaching in Cerebellar Ataxia
NCT03972202	Not specified	ACTIVE_NOT_RECRUITING	The Role of Cerebellum in Speech
NCT04010214	Not specified	RECRUITING	A Registered Cohort Study on Cerebellar Ataxia in the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR)
NCT04039048	Not specified	UNKNOWN	Effect of ctDCS During Balance Training on Cerebellar Ataxia
NCT04054726	Not specified	UNKNOWN	A Study on Cerebello-Spinal tPCS in Ataxia
NCT04529252	Not specified	ACTIVE_NOT_RECRUITING	Investigating the Genetic and Phenotypic Presentation of Ataxia and Nucleotide Repeat Diseases
NCT04648501	Not specified	COMPLETED	Dual Task Training for Cerebellar Ataxia
NCT04703595	Not specified	COMPLETED	Chronic Cough and CANVAS (Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome)
NCT04750850	Not specified	COMPLETED	Core Stability Exercises and Hereditary Ataxia
NCT04790981	Not specified	COMPLETED	Effect of Motor Imagery Training on Ataxic Children After Medulloblastoma Resection
NCT05002218	Not specified	COMPLETED	Training in Ataxia - Individuals With Degenerative Cerebellar Diseases
NCT05024240	Not specified	UNKNOWN	Interaction of the Cognitive and Sensory-cognitive Tasks With Postural Stability in Individuals With Stability Disorders
NCT05095870	Not specified	COMPLETED	Evaluation of the Peripheral Nerve Ultrasound as a Diagnostic Tool in CANVAS Neuropathies
NCT05132647	Not specified	UNKNOWN	Circular Timed Up and Go (cTUG) for Ataxia: Development and Validation
NCT05278091	Not specified	COMPLETED	Evaluation of the Diagnostic Value of Video-oculography in CANVAS Neuronopathies
NCT05351255	Not specified	ACTIVE_NOT_RECRUITING	Motor Learning After Cerebellar Damage: The Role of the Primary Motor Cortex
NCT05436262	Not specified	COMPLETED	Using Real-time fMRI Neurofeedback and Motor Imagery to Enhance Motor Timing and Precision in Cerebellar Ataxia
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry
NCT05625620	Not specified	UNKNOWN	Cerebellar-spinal Transcranial Pulsed Current Stimulation (tPCS) for Treatment of Neurodegenerative Ataxia
NCT05992207	Not specified	COMPLETED	Utilization of Motor Imagery Training for Improvement of Balance of Ataxic Children After Medulloblastoma Resection
NCT06152133	Not specified	COMPLETED	Telerehabilitation, Core Stability Exercises and Hereditary Ataxia (TRCore-ataxia)
NCT06450457	Not specified	COMPLETED	Effects of High Intensity Stepping Training on Gait in Patients With Ataxia