CP

protein-coding

ceruloplasmin

Gene summary

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. [provided by RefSeq, Feb 2012]

MANE transcript

NM_000096.4

Inheritance

AR, AD

ClinVar variants

P:105U:331B:155

Top phenotype

Aceruloplasminemia

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr3:149,162,410-149,221,829

External References & Databases

Ensembl (ENSG00000047457)

Transcript & Mutation Effects

hg38 • Region Span ~59.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

aceruloplasminemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011426

Submitter: Labcorp Genetics (formerly Invitae)

aceruloplasminemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011426

Submitter: Ambry Genetics

aceruloplasminemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011426

Submitter: ClinGen

*CP* was first reported in relation to autosomal recessive aceruloplasminemia in 1987 (Miyajima H et al., PMID: 3574673). Aceruloplasminemia is a disorder characterized by systemic and cerebral iron accumulation, with the classic clinical triad of retinal degeneration, diabetes mellitus and neurologic disease that typically manifests in individuals between their 30s and 70s. Neurologic features, including movement disorders (such as blepharospasm, grimacing, facial and cervical dystonia, tremor, and chorea) and ataxia (gait disturbance and dysarthria), reflect the distribution of iron deposition in the brain. Several variants (e.g., missense, splice site, frameshift) have been reported in multiple probands in four publications (PMID: 32235485; PMID: 29503155; PMID: 40043514; PMID: 3574673) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by animal models, where recessive, chemically induced mutant mice exhibit reduced iron oxidation and export from astrocytes to the blood-brain barrier (BBB), leading to decreased iron transfer to the brain (PMID: 40184642). Functional studies in HEK293T cells expressing wild-type and mutant ceruloplasmin, testing protein secretion, copper incorporation, and ferroxidase/oxidase activity, showed that several missense variants led to loss or reduction of ferroxidase activity (GO:0004322) and defective copper loading (GO:0005507), consistent with disease pathogenicity (PMID: 40043514). In summary, there is definitive evidence supporting the relationship between *CP* and autosomal recessive aceruloplasminemia. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen IEM GCEP at the meeting on October 10, 2025 (SOP Version 11).

disorder of iron metabolism and transportLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0017763

Submitter: Ambry Genetics

aceruloplasminemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011426

Submitter: Orphanet

aceruloplasminemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011426

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

AceruloplasminemiaAR

Manifestation: Biochemical; Endocrine; Gastrointestinal; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: In Aceruloplasminemia, medical management can be beneficial (eg, with iron chelating agents to decrease serum ferritin, brain and liver iron stores, and prevent progression of neurologic signs/symptoms; Combined IV desferrioxamine and fresh-frozen plasma can decrease liver iron content; repetitive FFP treatment can improve neurologic manifestations; antioxidants and oral zinc and deferasirox may prevent tissue damage to the liver and pancreas

Refs: 3574673; 1458725; 7820540; 7539672; 9066364; 20301666

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CP variants in ClinVar

9 Conditions Cataloged

Deficiency of ferroxidaseTotal: 520

not providedTotal: 168

Inborn genetic diseasesTotal: 146

not specifiedTotal: 53

CP-related disorderTotal: 38

Neurodegeneration with brain iron accumulationTotal: 8

CP-related disordersTotal: 3

Iron metabolism disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000096.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	126 clinvar	3 clinvar	138
missense	9 clinvar	12 clinvar	316 clinvar	24 clinvar	2 clinvar	363
nonsense	17 clinvar	8 clinvar				25
start loss		1 clinvar	1 clinvar			2
frameshift	30 clinvar	7 clinvar	1 clinvar			38
splice donor/acceptor (+/-2bp)	13 clinvar	8 clinvar	4 clinvar			25
Total	69	36	331	150	5	591

Highest pathogenic variant AF is 0.00009665248

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000096.4	RefSeq	NP_000087.2	19	MANE Select
ENST00000264613.11	Ensembl	ENSP00000264613.6	19	MANE Select
ENST00000455472.3	Ensembl	ENSP00000426888.1	4	Standard
ENST00000479771.5	Ensembl	ENSP00000420367.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cp	Danio rerio	Structure: otolith Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

Danio rerio

Structure: otolith

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Porphyrin and chlorophyll metabolism - Homo sapiens (human)
Ferroptosis - Homo sapiens (human)
Post-translational protein phosphorylation
Post-translational protein modification
Metabolism of proteins

Biological Process

copper ion transport
iron ion transport
cellular iron ion homeostasis
post-translational protein modification
cellular protein metabolic process

Molecular Function

ferroxidase activity
copper ion binding
oxidoreductase activity
chaperone binding

Cellular Component

extracellular region
extracellular space
lysosomal membrane
endoplasmic reticulum lumen
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264613
Coding exons: 19
Length: 59646
Individuals with no LoFs: 114812
Homozygous LoFs: 0
Heterozygous LoFs: 10936
Defined: 125748
p: 0.0445

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.223	550	565	0.974	0.0000281	7076
Missense (PolyPhen)		152	195.24	0.77853		2418
Synonymous	-1.09	221	201	1.10	0.0000109	1926
Loss of Function	3.66	25	54.1	0.462	0.00000262	689

Population LoF Frequency

Population	CAF	p-value	Status
African	0.035	0.036	notable
Latino/Admixed American	0.033	0.033	notable
Ashkenazi Jewish	0.037	0.037	notable
East Asian	0.035	0.035	notable
Finnish	0.040	0.040	notable
European (Non-Finnish)	0.055	0.056	notable
South Asian	0.033	0.033	notable
Other	0.049	0.049	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ceruloplasmin is a 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. Provides Cu(2+) ions for the ascorbate-mediated deaminase degradation of the heparan sulfate chains of GPC1. May also play a role in fetal lung development or pulmonary antioxidant defense (By similarity). {ECO:0000250}.;
Disease: DISEASE: Note=Ceruloplasmin levels are decreased in Wilson disease, in which copper cannot be incorporated into ceruloplasmin in liver because of defects in the copper-transporting ATPase 2.;

Recessive Scores

pRec: 0.673

Intolerance Scores

LoFtool: 0.0942
RVIS EVS: 0.25
RVIS percentile EVS: 69.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.928

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium