CPOX

Summary

CPOX (coproporphyrinogen oxidase, HGNC:2321) is a protein-coding gene on chromosome 3q11.2, encoding Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial (P36551). Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway. It is a selective cancer dependency (DepMap: 18.9% of cell lines).

The protein encoded by this gene is the sixth enzyme of the heme biosynthetic pathway. The encoded enzyme is soluble and found in the intermembrane space of mitochondria. This enzyme catalyzes the stepwise oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX, a precursor of heme. Defects in this gene are a cause of hereditary coproporphyria (HCP).

Source: NCBI Gene 1371 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CPOX-related hereditary coproporphyria (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 410 total — 30 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 66
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 18.9% of screened cell lines
• MANE Select transcript: NM_000097

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2321
Approved symbol	CPOX
Name	coproporphyrinogen oxidase
Location	3q11.2
Locus type	gene with protein product
Status	Approved
Aliases	CPX, HCP
Ensembl gene	ENSG00000080819
Ensembl biotype	protein_coding
OMIM	612732
Entrez	1371

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000510489, ENST00000513674, ENST00000515041, ENST00000647941, ENST00000890710, ENST00000890711, ENST00000890712, ENST00000932270, ENST00000946176

RefSeq mRNA: 1 — MANE Select: NM_000097 NM_000097

CCDS: CCDS2932

Canonical transcript exons

ENST00000647941 — 7 exons

Exon	Start	End
ENSE00000520584	98585441	98585659
ENSE00000774428	98590632	98590742
ENSE00000774429	98588713	98588854
ENSE00000817865	98579446	98580770
ENSE00003683221	98591012	98591155
ENSE00003836981	98592949	98593611
ENSE00003837618	98581407	98581511

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 96.95.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0470 / max 74.7713, expressed in 3 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43379	18.3226	1805
43380	1.1816	814
43381	1.1247	686
43382	0.1462	64
24841	0.0470	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	96.95	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.73	gold quality
jejunal mucosa	UBERON:0000399	92.44	gold quality
spinal cord	UBERON:0002240	92.37	gold quality
lower esophagus mucosa	UBERON:0035834	91.23	gold quality
corpus callosum	UBERON:0002336	91.14	gold quality
right lobe of liver	UBERON:0001114	91.05	gold quality
bone marrow	UBERON:0002371	90.59	gold quality
inferior vagus X ganglion	UBERON:0005363	88.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.21	gold quality
bone marrow cell	CL:0002092	87.71	gold quality
liver	UBERON:0002107	87.43	gold quality
rectum	UBERON:0001052	87.37	gold quality
monocyte	CL:0000576	87.28	gold quality
duodenum	UBERON:0002114	87.25	gold quality
mononuclear cell	CL:0000842	87.09	gold quality
leukocyte	CL:0000738	86.85	gold quality
substantia nigra	UBERON:0002038	86.64	gold quality
esophagus mucosa	UBERON:0002469	86.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.55	gold quality
stromal cell of endometrium	CL:0002255	85.98	gold quality
midbrain	UBERON:0001891	85.97	gold quality
Ammon’s horn	UBERON:0001954	85.46	gold quality
adrenal tissue	UBERON:0018303	85.24	gold quality
esophagus squamous epithelium	UBERON:0006920	85.06	gold quality
granulocyte	CL:0000094	84.95	gold quality
CA1 field of hippocampus	UBERON:0003881	84.82	gold quality
inferior olivary complex	UBERON:0002127	84.54	gold quality
prefrontal cortex	UBERON:0000451	84.43	gold quality
hypothalamus	UBERON:0001898	84.33	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	545.23
E-CURD-112	yes	49.93
E-MTAB-10042	yes	40.76
E-MTAB-9388	yes	9.02
E-ANND-3	yes	7.87
E-HCAD-9	yes	6.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1, MEF2A, NFE2L2, NRF1, PPARA, SP1, SP3, SP4, TCF3, YY1

miRNA regulators (miRDB)

86 targeting CPOX, 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-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 18.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• disease-producing mutations in the CPO gene in nine Swedish families with hereditary coproporphyria (PMID:12181641)
• coproporphyrinogen III oxidase sequence matches many structural features from urate oxidase (PMID:12208494)
• Modulation of penetrance by the wild-type allele in dominantly inherited erythrohepatic and acute hepatic porphyrias was studied using CPO. (PMID:14669009)
• All other type of mutations or missense mutations mapped elsewhere throughout the CPO gene, lead to coproporphyrin accumulation and subsequently typical HCP. (PMID:16159891)
• CPO mutations form the structural basis of hereditary coproporphyria. (PMID:16176984)
• The Km recognition) and Kcat values for coproporphyrinogen III and IV were determined. (PMID:16258391)
• His158 of human CPO may have a role in the active site, but none of the conserved histidine residues of human coproporphyrinogen oxidase is essential for catalytic activity. (PMID:17179900)
• The authors report the association of a novel mutation in the coproporphyrinogen oxidase gene in an Irish pedigree with the devlopment of hereditary coproporphyria (PMID:18557518)
• Three of the novel missense mutations and one frameshift mutation was detected in coproporphyrinogen III oxidase (CPO) gene in five Italian patients affected by Hereditary Coproporphyria (HCP). (PMID:19267996)
• biochemical & kinetic properties of CPOX4, the product of a polymorphism of the CPOX gene that modifies effects of mercury on neurobehavioral function; suggests CPOX4 may predispose to impaired heme biosynthesis which is limited further by Hg exposure (PMID:19339664)
• Deletion of the fifth exon in the CPOX gene is associated with hereditary coproporphyria. (PMID:21231929)
• competitive action of both uroporphyrinogen decarboxylase and CPO on the same diacetate porphyrinogen substrate provides additional perspectives on the potential existence of abnormal pathways for heme biosynthesis (PMID:21277781)
• CPOX polymorphisms are associated with biological media contamination and apoptosis disorders. (PMID:22288185)
• Polymorphism of coproporphyrinogen oxidase is associated with genetic susceptibility to the adverse neurobehavioral effects of Hg exposure in children. (PMID:22765978)
• The monomer form of mutated CPOX did not show any activity and homodimeric enzymes derived from Hereditary coproporphyria (HCP) mutant showed low activity (<20% of the control). (PMID:24078084)
• Mount Sinai Porphyrias Diagnostic Laboratory diagnosed 29 unrelated Hereditary Coproporphyria individuals with 11 previously unreported CPOX mutations. (PMID:30385147)
• TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer’s disease biomarker levels. (PMID:33991015)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cpox	ENSDARG00000062025
mus_musculus	Cpox	ENSMUSG00000022742
rattus_norvegicus	Cpox	ENSRNOG00000001654
drosophila_melanogaster	Coprox	FBGN0021944

Protein

Protein identifiers

Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial — P36551 (reviewed: P36551)

All UniProt accessions (2): P36551, D6RER6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion intermembrane space.

Disease relevance. Hereditary coproporphyria (HCP) [MIM:121300] A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Hereditary coproporphyria is an acute hepatic porphyria characterized by skin photosensitivity, attacks of abdominal pain, neurological disturbances, and psychiatric symptoms. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors. Hereditary coproporphyria is biochemically characterized by overexcretion of coproporphyrin III in the urine and in the feces. The disease is caused by variants affecting the gene represented in this entry. Harderoporphyria (HARPO) [MIM:618892] An autosomal recessive form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. HARPO is a rare erythropoietic variant form characterized by neonatal hemolytic anemia, sometimes accompanied by skin lesions, and massive excretion of harderoporphyrin in feces. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; protoporphyrinogen-IX from coproporphyrinogen-III (O2 route): step 1/1.

Similarity. Belongs to the aerobic coproporphyrinogen-III oxidase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P36551-1	1	yes
P36551-2	2

RefSeq proteins (1): NP_000088* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001260	Coprogen_oxidase_aer	Family
IPR018375	Coprogen_oxidase_CS	Conserved_site
IPR036406	Coprogen_oxidase_aer_sf	Homologous_superfamily

Pfam: PF01218

Enzyme classification (BRENDA):

• EC 1.3.3.3 — coproporphyrinogen oxidase (BRENDA: 28 organisms, 110 substrates, 65 inhibitors, 83 Km, 35 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
COPROPORPHYRINOGEN-III	0.0001–0.32	52
HARDEROPORPHYRINOGEN	0.0001–0.044	5
COPROPORPHYRINOGEN III	0.0001–0.0151	4
COPROPORPHYRINOGEN-IV	0.0006–0.0008	3
3-[7-(2-CARBOXY-ETHYL)-13,17-DIETHYL-3,8,12,18-T	0.0006–0.001	2
MESOPORPHYRINOGEN-VI	0.0006–0.002	2
PENTACARBOXYLATE PORPHYRINOGEN 5DAB	0.0013	2
3-[7,13-DI(2-CARBOXY-ETHYL)-17-BENZYL-3,8,12,18-	0.002	1
3-[7,13-DI(2-CARBOXY-ETHYL)-17-ETHYL-3,8,12,18-T	—	1
3-[7,17-DI(2-CARBOXY-ETHYL)-13-BENZYL-3,8,12,18-	0.0009	1
3-[7,17-DI(2-CARBOXY-ETHYL)-13-ETHYL-3,8,12,18-T	0.0008	1
3-[7-(2-CARBOXY-ETHYL)-13,17-DI-TERT-BUTYL-3,8,1	0.0001	1
3-[7-(2-CARBOXY-ETHYL)-13,17-DIBUTYL-3,8,12,18-T	0.011	1
3-[7-(2-CARBOXY-ETHYL)-13,17-DIISOPROPYL-3,8,12,	0.0003	1
3-[7-(2-CARBOXY-ETHYL)-13,17-DIPROPYL-3,8,12,18-	0.011	1

Catalyzed reactions (Rhea), 1 shown:

• coproporphyrinogen III + O2 + 2 H(+) = protoporphyrinogen IX + 2 CO2 + 2 H2O (RHEA:18257)

UniProt features (63 total): sequence variant 23, helix 13, strand 9, modified residue 3, region of interest 3, binding site 3, splice variant 2, transit peptide 1, chain 1, mutagenesis site 1, sequence conflict 1, turn 1, active site 1, site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2AEX	X-RAY DIFFRACTION	1.58

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36551-F1	80.32	0.63

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 (2): 258 (proton donor); 327 (important for dimerization)

Ligand- & substrate-binding residues (3): 244; 260–262; 411–413

Post-translational modifications (3): 112, 404, 404

Mutagenesis-validated functional residues (1):

Position	Phenotype
392–418	loss for dimerization.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis

MSigDB gene sets: 354 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8A_DC_DN, GOMF_METALLOPEPTIDASE_ACTIVITY, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, REACTOME_METABOLISM_OF_PORPHYRINS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, GOLDRATH_ANTIGEN_RESPONSE, GOBP_RESPONSE_TO_METAL_ION, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, SMITH_TERT_TARGETS_DN

GO Biological Process (10): obsolete protoporphyrinogen IX biosynthetic process (GO:0006782), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), heme B biosynthetic process (GO:0006785), response to iron ion (GO:0010039), response to lead ion (GO:0010288), response to insecticide (GO:0017085), response to arsenic-containing substance (GO:0046685), response to methylmercury (GO:0051597), porphyrin-containing compound biosynthetic process (GO:0006779)

GO Molecular Function (5): coproporphyrinogen oxidase activity (GO:0004109), structural constituent of eye lens (GO:0005212), protein homodimerization activity (GO:0042803), oxidoreductase activity (GO:0016491), identical protein binding (GO:0042802)

GO Cellular Component (6): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of porphyrins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
heme biosynthetic process	2
response to metal ion	2
response to chemical	2
cytoplasm	2
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
response to toxic substance	1
porphyrin-containing compound metabolic process	1
tetrapyrrole biosynthetic process	1
oxidoreductase activity, acting on the CH-CH group of donors, oxygen as acceptor	1
structural molecule activity	1
identical protein binding	1
protein dimerization activity	1
catalytic activity	1
protein binding	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial envelope	1
organelle envelope lumen	1

Protein interactions and networks

STRING

1854 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPOX	UROD	P06132	976
CPOX	ALAD	P13716	971
CPOX	FECH	P22830	970
CPOX	HMBS	P08396	926
CPOX	PPOX	P50336	920
CPOX	UROS	P10746	913
CPOX	ALAS1	P13196	794
CPOX	ALAS2	P22557	769
CPOX	SLC25A37	Q9NYZ2	719
CPOX	MTCP1	P56278	703
CPOX	HMOX2	P30519	684
CPOX	SLC25A38	Q96DW6	647
CPOX	ABCB6	Q9NP58	636
CPOX	ACO2	Q99798	616
CPOX	FXN	Q16595	608

IntAct

47 interactions, top by confidence:

A	B	Type	Score
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
AIFM1	SEC16A	psi-mi:“MI:2364”(proximity)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
	DENR	psi-mi:“MI:0915”(physical association)	0.400
UBE2G2	CPOX	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
CPOX	Fech	psi-mi:“MI:0914”(association)	0.350
TCF4	OGT	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
STYX	BANF1	psi-mi:“MI:0914”(association)	0.350
PAK4	SNRPE	psi-mi:“MI:0914”(association)	0.350
SLC25A25	HAX1	psi-mi:“MI:0914”(association)	0.350
	SYNCRIP	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
	TUB4q	psi-mi:“MI:0914”(association)	0.350
	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
	HNRNPR	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
RBPMS	CA2	psi-mi:“MI:0914”(association)	0.350
TTC9C		psi-mi:“MI:0914”(association)	0.350
HRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350

BioGRID (114): C10orf2 (Co-fractionation), TRNT1 (Co-fractionation), YARS (Co-fractionation), CPOX (Affinity Capture-MS), CPOX (Affinity Capture-MS), CPOX (Affinity Capture-MS), CPOX (Affinity Capture-MS), CPOX (Affinity Capture-MS), CPOX (Affinity Capture-MS), CPOX (Affinity Capture-MS), CPOX (Proximity Label-MS), CPOX (Proximity Label-MS), CPOX (Proximity Label-MS), CPOX (Proximity Label-MS), CPOX (Proximity Label-MS)

ESM2 similar proteins: A3RM19, A4IFN2, A4UHQ3, A6NNL5, E1C762, O12165, O55611, O75489, P06025, P06501, P0DOF3, P11824, P15197, P16285, P23709, P24932, P29917, P36551, P49408, P84066, Q04350, Q08314, Q09110, Q0GBX9, Q0GBY4, Q0MQG6, Q0MQG7, Q0MQG8, Q10588, Q14BA6, Q24434, Q29498, Q42840, Q42946, Q4V7D2, Q5VYS4, Q66453, Q68667, Q68668, Q68669

Diamond homologs: A0KEX7, A0KR67, A0Q6H6, A1RDY8, A1S1K6, A1V2G0, A2BTG1, A2BYW5, A2C524, A2S4B5, A3CYL1, A3MI45, A3N7F7, A3NT46, A3PF71, A4IY09, A4ST50, A4VFI3, A4XNB8, A4Y1D3, A5IBB3, A5VWK4, A6TC68, A6UX86, A6WHB7, A7MKX5, A7NC51, A8FP82, A8G786, A8GYI0, A9AJJ8, A9ITM7, B0KF35, B0TLD7, B0U151, B1J4A2, B1JW43, B1LMN0, B1YU52, B2SGG9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein degradation	5	20.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	9
Uncertain significance	229
Likely benign	57
Benign	42

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070944	NM_000097.7(CPOX):c.139_151dup (p.Pro51fs)	Pathogenic
1074990	NM_000097.7(CPOX):c.79_83dup (p.Gln29fs)	Pathogenic
1076524	NM_000097.7(CPOX):c.152del (p.Pro51fs)	Pathogenic
1076606	NM_000097.7(CPOX):c.661_665del (p.Gln221fs)	Pathogenic
126445	NM_000097.7(CPOX):c.980A>G (p.His327Arg)	Pathogenic
1322158	NM_000097.7(CPOX):c.953+2T>C	Pathogenic
1353614	NM_000097.7(CPOX):c.1063C>T (p.Gln355Ter)	Pathogenic
1444842	NM_000097.7(CPOX):c.638del (p.Asn213fs)	Pathogenic
1454519	NC_000003.11:g.(?98299527)(98304523_?)del	Pathogenic
1456595	NM_000097.7(CPOX):c.32del (p.Gly11fs)	Pathogenic
1457857	NM_000097.7(CPOX):c.1268dup (p.Thr424fs)	Pathogenic
149128	GRCh38/hg38 3q11.2-13.31(chr3:97795369-115663349)x1	Pathogenic
2864548	NM_000097.7(CPOX):c.871G>T (p.Glu291Ter)	Pathogenic
2867487	NM_000097.7(CPOX):c.645del (p.Glu216fs)	Pathogenic
3496547	NM_000097.7(CPOX):c.824G>A (p.Trp275Ter)	Pathogenic
3496548	NM_000097.7(CPOX):c.525del (p.Ser177fs)	Pathogenic
3894555	NM_000097.7(CPOX):c.661C>T (p.Gln221Ter)	Pathogenic
452	NM_000097.7(CPOX):c.1277G>A (p.Arg426Gln)	Pathogenic
454	NM_000097.7(CPOX):c.127_131dup (p.Gly45fs)	Pathogenic
455	NM_000097.7(CPOX):c.489_509del (p.Cys164_Val170del)	Pathogenic
456	NM_000097.7(CPOX):c.883C>G (p.His295Asp)	Pathogenic
458	NM_000097.7(CPOX):c.85C>T (p.Gln29Ter)	Pathogenic
460	NM_000097.7(CPOX):c.623C>T (p.Ser208Phe)	Pathogenic
461	NM_000097.7(CPOX):c.982C>T (p.Arg328Cys)	Pathogenic
462	NM_000097.7(CPOX):c.856dup (p.Thr286fs)	Pathogenic
463	NM_000097.7(CPOX):c.835G>C (p.Gly279Arg)	Pathogenic
4774154	NM_000097.7(CPOX):c.647_648del (p.Glu216fs)	Pathogenic
650602	NM_000097.7(CPOX):c.225del (p.Thr76fs)	Pathogenic
656587	NM_000097.7(CPOX):c.717T>A (p.Cys239Ter)	Pathogenic
801990	NM_000097.7(CPOX):c.478C>T (p.Gln160Ter)	Pathogenic

SpliceAI

1323 predictions. Top by Δscore:

Variant	Effect	Δscore
3:98580782:C:CT	acceptor_gain	1.0000
3:98580782:C:T	acceptor_gain	1.0000
3:98581440:T:A	donor_gain	1.0000
3:98585435:ACTT:A	donor_loss	1.0000
3:98585436:CTTA:C	donor_loss	1.0000
3:98585437:TTA:T	donor_loss	1.0000
3:98585438:T:TG	donor_loss	1.0000
3:98585439:A:AC	donor_gain	1.0000
3:98585439:ACCGT:A	donor_gain	1.0000
3:98585440:C:CC	donor_gain	1.0000
3:98585440:C:CG	donor_loss	1.0000
3:98585440:CCGT:C	donor_gain	1.0000
3:98585440:CCGTC:C	donor_gain	1.0000
3:98585691:CAAA:C	acceptor_gain	1.0000
3:98591007:TTTAC:T	donor_loss	1.0000
3:98591008:TTA:T	donor_loss	1.0000
3:98591009:TACC:T	donor_loss	1.0000
3:98591010:A:AT	donor_loss	1.0000
3:98591153:CTC:C	acceptor_gain	1.0000
3:98591162:A:C	acceptor_gain	1.0000
3:98591168:A:AC	acceptor_gain	1.0000
3:98591168:A:C	acceptor_gain	1.0000
3:98580773:A:C	acceptor_gain	0.9900
3:98580777:A:C	acceptor_gain	0.9900
3:98580783:A:T	acceptor_gain	0.9900
3:98585439:AC:A	donor_gain	0.9900
3:98585440:CC:C	donor_gain	0.9900
3:98585440:CCG:C	donor_gain	0.9900
3:98585657:CAC:C	acceptor_gain	0.9900
3:98585660:CTG:C	acceptor_loss	0.9900

AlphaMissense

2944 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:98580769:A:G	W427R	0.999
3:98580769:A:T	W427R	0.999
3:98581469:A:C	F405L	0.999
3:98581469:A:T	F405L	0.999
3:98581471:A:G	F405L	0.999
3:98581485:T:A	D400V	0.999
3:98581499:A:C	F395L	0.999
3:98581499:A:T	F395L	0.999
3:98581501:A:G	F395L	0.999
3:98590663:G:C	N260K	0.999
3:98590663:G:T	N260K	0.999
3:98590701:G:C	H248D	0.999
3:98590711:G:C	S244R	0.999
3:98590711:G:T	S244R	0.999
3:98590713:T:G	S244R	0.999
3:98580767:C:A	W427C	0.998
3:98580767:C:G	W427C	0.998
3:98581419:G:C	P422R	0.998
3:98581419:G:T	P422H	0.998
3:98581485:T:G	D400A	0.998
3:98581494:A:G	L397P	0.998
3:98581496:A:C	N396K	0.998
3:98581496:A:T	N396K	0.998
3:98585656:A:C	C319W	0.998
3:98590658:C:G	R262T	0.998
3:98590671:G:C	H258D	0.998
3:98590729:A:C	F238L	0.998
3:98590729:A:T	F238L	0.998
3:98590731:A:G	F238L	0.998
3:98581410:G:T	A425D	0.997

dbSNP variants (sampled 300 via entrez): RS1000315871 (3:98583112 G>A), RS1000372201 (3:98578666 A>G), RS1000653721 (3:98582135 T>C), RS1000761517 (3:98571596 G>A,T), RS1000831303 (3:98576958 G>T), RS1000987850 (3:98577293 T>C,G), RS1001009347 (3:98593499 G>A), RS1001076198 (3:98582965 A>G), RS1001107786 (3:98577540 T>C), RS1001123789 (3:98593615 C>G,T), RS1001289957 (3:98576248 G>A), RS1001374676 (3:98588060 A>G), RS1001388100 (3:98587710 C>T), RS1001490582 (3:98593662 G>A), RS1001721463 (3:98575978 A>G)

Disease associations

OMIM: gene MIM:612732 | disease phenotypes: MIM:121300, MIM:618892, MIM:176000

GenCC curated gene-disease

Disease	Classification	Inheritance
harderoporphyria	Strong	Autosomal recessive
hereditary coproporphyria	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
CPOX-related hereditary coproporphyria	Definitive	SD

Mondo (4): hereditary coproporphyria (MONDO:0007369), harderoporphyria (MONDO:0030048), CPOX-related hereditary coproporphyria (MONDO:0800180), acute intermittent porphyria (MONDO:0008294)

Orphanet (3): Harderoporphyria (Orphanet:659672), Hereditary coproporphyria (Orphanet:79273), Acute intermittent porphyria (Orphanet:79276)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000112	Nephropathy
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000822	Hypertension
HP:0000952	Jaundice
HP:0000953	Hyperpigmentation of the skin
HP:0000987	Atypical scarring of skin
HP:0000992	Cutaneous photosensitivity
HP:0001030	Fragile skin
HP:0001250	Seizure
HP:0001289	Confusion
HP:0001402	Hepatocellular carcinoma
HP:0001649	Tachycardia
HP:0001744	Splenomegaly
HP:0001878	Hemolytic anemia
HP:0001903	Anemia
HP:0001923	Reticulocytosis
HP:0001945	Fever
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002093	Respiratory insufficiency
HP:0002203	Respiratory paralysis
HP:0002240	Hepatomegaly

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001521_28	Subcutaneous adipose tissue	4.000000e-06
GCST006463_3	Urinary albumin excretion (no hypertensive medication)	5.000000e-08
GCST010002_434	Refractive error	5.000000e-25

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004285	albuminuria

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D046349	Coproporphyria, Hereditary	C06.552.830.074; C16.320.850.742.074; C17.800.827.742.074; C18.452.811.400.074
D017118	Porphyria, Acute Intermittent	C06.552.830.150; C16.320.850.742.150; C17.800.827.742.150; C18.452.811.400.150
C562816	Harderoporphyria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1681618 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	6
bisphenol A	affects expression, affects cotreatment, decreases methylation, increases expression	4
Mercury	increases abundance, affects response to substance, decreases carboxylation, decreases reaction, increases chemical synthesis (+1 more)	3
isocoproporphyrin	affects abundance, increases chemical synthesis	2
protoporphyrinogen	increases chemical synthesis, decreases reaction, increases reaction	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
coproporphyrinogen III	decreases carboxylation, decreases reaction	1
pentacarboxylic porphyrin	increases metabolic processing	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1676173	Binding	Activity at recombinant human CPO	Normal and abnormal heme biosynthesis. Part 7. Synthesis and metabolism of coproporphyrinogen-III analogues with acetate or butyrate side chains on rings C and D. Development of a modified model for the active site of coproporphyrinogen oxidase. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C6IL	U87MG/CPOX-KO	Cancer cell line	Male
CVCL_E1UK	HAP1 CPOX (-) 1	Cancer cell line	Male
CVCL_E1UL	HAP1 CPOX (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03338816	PHASE3	COMPLETED	ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
NCT02922413	PHASE2	TERMINATED	Panhematin for Prevention of Acute Attacks of Porphyria
NCT02082860	PHASE1	COMPLETED	Phase I Gene Therapy Clinical Trial Using the Vector rAAV2/5-PBGD for the Treatment of Acute Intermittent Porphyria
NCT02452372	PHASE1	COMPLETED	A Phase 1 Study of Givosiran (ALN-AS1) in Patients With Acute Intermittent Porphyria (AIP)
NCT02943213	PHASE1	COMPLETED	Assessment of Intra-subject Variability in the Bioavailability of Chlorpromazine Hydrochloride
NCT03505853	PHASE1	COMPLETED	A Study to Investigate the Interaction Between Givosiran and a 5-probe Drug Cocktail in Patients With Acute Intermittent Porphyria (AIP)
NCT01568554	Not specified	COMPLETED	Clinical Diagnosis of Acute Porphyria
NCT02935400	Not specified	ACTIVE_NOT_RECRUITING	Acute Porphyria Biomarkers for Disease Activity
NCT03547297	Not specified	TERMINATED	INSIGHT-AHP: A Study to Characterize the Prevalence of Acute Hepatic Porphyria (AHP) in Patients With Clinical Presentation and History Consistent With AHP
NCT00418795	PHASE2/PHASE3	COMPLETED	Porphozym in the Treatment of Acute Attacks in AIP
NCT02949830	PHASE1/PHASE2	COMPLETED	A Study to Evaluate Long-term Safety and Clinical Activity of Givosiran (ALN-AS1) in Patient With Acute Intermittent Porphyria (AIP)
NCT01617642	Not specified	ACTIVE_NOT_RECRUITING	Dental Health, Diet, Inflammation and Biomarkers in Patients With Acute Intermittent Porphyria(AIP)
NCT02076763	Not specified	COMPLETED	Observational Study of Acute Intermittent Porphyria Patients
NCT05502133	Not specified	RECRUITING	Identification of Acute Intermittent Porphyria Modifying Genes
NCT06273644	Not specified	RECRUITING	Clinical Research on Acute Intermittent Porphyria and the Use of Carbohydrate-Rich Diet as a Treatment