COX5A

Summary

COX5A (cytochrome c oxidase subunit 5A, HGNC:2267) is a protein-coding gene on chromosome 15q24.2, encoding Cytochrome c oxidase subunit 5A, mitochondrial (P20674). Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. It is a selective cancer dependency (DepMap: 61.3% of cell lines).

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit Va of the human mitochondrial respiratory chain enzyme. A pseudogene COX5AP1 has been found in chromosome 14q22.

Source: NCBI Gene 9377 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Moderate, ClinGen) — +2 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 45 total — 2 pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 61.3% of screened cell lines
• MANE Select transcript: NM_004255

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2267
Approved symbol	COX5A
Name	cytochrome c oxidase subunit 5A
Location	15q24.2
Locus type	gene with protein product
Status	Approved
Aliases	COX-VA
Ensembl gene	ENSG00000178741
Ensembl biotype	protein_coding
OMIM	603773
Entrez	9377

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 12 protein_coding

ENST00000322347, ENST00000562233, ENST00000564811, ENST00000567270, ENST00000568517, ENST00000568783, ENST00000873796, ENST00000873797, ENST00000933589, ENST00000961788, ENST00000961789, ENST00000961790

RefSeq mRNA: 1 — MANE Select: NM_004255 NM_004255

CCDS: CCDS10273

Canonical transcript exons

ENST00000322347 — 5 exons

Exon	Start	End
ENSE00001243524	74919791	74920442
ENSE00001243548	74923648	74923770
ENSE00001296442	74937915	74938073
ENSE00003498206	74929116	74929232
ENSE00003664819	74926766	74926887

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 268.3110 / max 1744.0024, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150941	265.9589	1828
150942	2.3521	1280

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.83	gold quality
cardiac ventricle	UBERON:0002082	99.72	gold quality
heart left ventricle	UBERON:0002084	99.72	gold quality
biceps brachii	UBERON:0001507	99.70	gold quality
mucosa of transverse colon	UBERON:0004991	99.70	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.70	gold quality
right atrium auricular region	UBERON:0006631	99.68	gold quality
apex of heart	UBERON:0002098	99.67	gold quality
colonic mucosa	UBERON:0000317	99.66	gold quality
diaphragm	UBERON:0001103	99.66	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.65	gold quality
jejunal mucosa	UBERON:0000399	99.63	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.56	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.53	gold quality
body of tongue	UBERON:0011876	99.53	gold quality
epithelium of nasopharynx	UBERON:0001951	99.51	gold quality
adult organism	UBERON:0007023	99.46	gold quality
jejunum	UBERON:0002115	99.44	gold quality
gluteal muscle	UBERON:0002000	99.41	gold quality
gingival epithelium	UBERON:0001949	99.40	gold quality
rectum	UBERON:0001052	99.38	gold quality
gastrocnemius	UBERON:0001388	99.37	gold quality
triceps brachii	UBERON:0001509	99.36	gold quality
esophagus squamous epithelium	UBERON:0006920	99.33	gold quality
heart	UBERON:0000948	99.32	gold quality
transverse colon	UBERON:0001157	99.31	gold quality
epithelium of esophagus	UBERON:0001976	99.30	gold quality
endothelial cell	CL:0000115	99.29	gold quality
left testis	UBERON:0004533	99.29	gold quality
right testis	UBERON:0004534	99.29	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	22.38
E-CURD-46	yes	20.51
E-MTAB-8410	yes	19.36
E-MTAB-10042	yes	17.06
E-CURD-112	yes	9.66
E-MTAB-10596	no	681.63
E-GEOD-125970	no	41.82
E-CURD-120	no	35.85
E-GEOD-83139	no	2.87
E-HCAD-31	no	2.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FLCN, TRPV4

miRNA regulators (miRDB)

34 targeting COX5A, 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-607	99.97	73.62	5593
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-5697	99.39	67.74	1249
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-3908	98.75	67.31	1160

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 61.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• study points to a role for surfeit 1(SURF1) in promoting the association of cytochrome c oxidase II with the cytochrome c oxidase I.cytochrome c oxidase subunit 4.cytochrome c oxidase subunit 5A subassembly (PMID:14607829)
• Data show that Bcl-2 expression positively influences the targeting of nuclear-encoded COX Va and Vb to the mitochondria of cancer cells. (PMID:19834492)
• Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 5a (PMID:20307258)
• Our current study showed that COX Va may play a role in migration and invasion of NSCLC cells and can be used as a biomarker to predict aggressiveness of NSCLC. (PMID:22748147)
• The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts. (PMID:28247525)
• miR-204/COX5A axis contributes to invasion and chemotherapy resistance in estrogen receptor-positive breast cancers. (PMID:32758616)
• COX5A Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress, Mitochondrial Dysfunction and Cardiomyocyte Apoptosis. (PMID:37373547)
• COX5A as a potential biomarker for disease activity and organ damage in lupus. (PMID:37891386)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cox5aa	ENSDARG00000088383
danio_rerio	cox5ab	ENSDARG00000099663
mus_musculus	Cox5a	ENSMUSG00000000088
rattus_norvegicus	LOC100361008	ENSRNOG00000018816
rattus_norvegicus	LOC100361008	ENSRNOG00000022490
drosophila_melanogaster	COX5A	FBGN0019624
caenorhabditis_elegans		WBGENE00012553

Protein

Protein identifiers

Cytochrome c oxidase subunit 5A, mitochondrial — P20674 (reviewed: P20674)

Alternative names: Cytochrome c oxidase polypeptide Va

All UniProt accessions (5): P20674, H3BNX8, H3BRI0, H3BRM5, H3BV69

UniProt curated annotations — full annotation on UniProt →

Function. Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.

Subunit / interactions. Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and COXFA4, which are encoded in the nuclear genome. The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)). Interacts with AFG1L. Interacts with RAB5IF.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. In response to mitochondrial stress, the precursor protein is ubiquitinated by the SIFI complex in the cytoplasm before mitochondrial import, leading to its degradation. Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 20 (MC4DN20) [MIM:619064] An autosomal recessive mitochondrial disorder with onset in early infancy. MC4DN20 is characterized by pulmonary arterial hypertension, poor feeding, failure to thrive, hypotonia, delayed development, increased serum lactate and metabolic acidosis. Death in infancy occurs due to cardiorespiratory failure. Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV. The disease may be caused by variants affecting the gene represented in this entry.

Pathway. Energy metabolism; oxidative phosphorylation.

Similarity. Belongs to the cytochrome c oxidase subunit 5A family.

RefSeq proteins (1): NP_004246* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003204	Cyt_c_oxidase_su5A/6	Family
IPR036545	Cyt_c_oxidase_su5A/6_sf	Homologous_superfamily

Pfam: PF02284

UniProt features (8 total): modified residue 3, transit peptide 1, chain 1, short sequence motif 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9I6F	ELECTRON MICROSCOPY	2.95
9I7U	ELECTRON MICROSCOPY	3.15
5Z62	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20674-F1	88.21	0.72

Functional residue map

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

Post-translational modifications (3): 87, 113, 141

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-611105	Respiratory electron transport
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 318 (showing top): MORF_MTA1, MORF_MBD4, MORF_RAB5A, MORF_RAD21, MORF_PSMC2, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, MORF_SKP1A, MORF_ATOX1, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_ELECTRON_TRANSPORT_CHAIN, KEGG_HUNTINGTONS_DISEASE, MODULE_307, MORF_PPP6C, GOCC_MITOCHONDRIAL_ENVELOPE

GO Biological Process (4): mitochondrial electron transport, cytochrome c to oxygen (GO:0006123), cellular respiration (GO:0045333), oxidative phosphorylation (GO:0006119), proton transmembrane transport (GO:1902600)

GO Molecular Function (4): cytochrome-c oxidase activity (GO:0004129), electron transfer activity (GO:0009055), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), mitochondrial membrane (GO:0031966), respiratory chain complex IV (GO:0045277), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Transcriptional Regulation by TP53	1
Aerobic respiration and respiratory electron transport	1
Cellular response to chemical stress	1
Metabolism of proteins	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrial envelope	2
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
energy derivation by oxidation of organic compounds	1
aerobic respiration	1
proton motive force-driven ATP synthesis	1
monoatomic cation transmembrane transport	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on a heme group of donors	1
active monoatomic ion transmembrane transporter activity	1
molecular_function	1
cation binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
organelle envelope lumen	1
mitochondrion	1
organelle membrane	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2314 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX5A	COX4I1	P13073	992
COX5A	COX5B	P10606	988
COX5A	COX6B1	P14854	970
COX5A	COX6A1	P12074	959
COX5A	COX6C	P09669	955
COX5A	COX6A2	Q02221	911
COX5A	COX4I2	Q96KJ9	894
COX5A	HIGD1A	Q9Y241	890
COX5A	COX8A	P10176	842
COX5A	COX7C	P15954	839
COX5A	MT-CO1	P00395	830
COX5A	MT-CO2	P00403	787
COX5A	COX15	Q7KZN9	782
COX5A	ATP5F1B	P06576	776
COX5A	ATP5PD	O75947	775

IntAct

135 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
RAC1	COX6C	psi-mi:“MI:0914”(association)	0.640
COA3	MT-CO1	psi-mi:“MI:0914”(association)	0.610
KRT31	COX5A	psi-mi:“MI:0915”(physical association)	0.560
KRT40	COX5A	psi-mi:“MI:0915”(physical association)	0.560
EXOSC8	COX5A	psi-mi:“MI:0915”(physical association)	0.560
COX5A	KRT40	psi-mi:“MI:0915”(physical association)	0.560
COX5A	EXOSC8	psi-mi:“MI:0915”(physical association)	0.560
SPDEF	COX5A	psi-mi:“MI:0915”(physical association)	0.560
COX5A	MESD	psi-mi:“MI:0915”(physical association)	0.560
PIK3R1	COX5A	psi-mi:“MI:0915”(physical association)	0.560
APP	COX5A	psi-mi:“MI:0915”(physical association)	0.560
MT-CO2	COX6C	psi-mi:“MI:0915”(physical association)	0.560
G3BP1	COX5A	psi-mi:“MI:0914”(association)	0.530
COX5A	COX7A2L	psi-mi:“MI:0914”(association)	0.530
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
COX5A	PDE4DIP	psi-mi:“MI:0915”(physical association)	0.370
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
Cenpe	BBX	psi-mi:“MI:0914”(association)	0.350

BioGRID (276): COX5A (Two-hybrid), EXOSC8 (Two-hybrid), KRT40 (Two-hybrid), COX5A (Affinity Capture-MS), COX5A (Affinity Capture-RNA), COX5A (Co-fractionation), COX5A (Co-fractionation), COX5A (Co-fractionation), COX5A (Co-fractionation), COX5A (Co-fractionation), COX5A (Co-fractionation), COX5A (Co-fractionation), COX5A (Co-fractionation), COX5A (Co-fractionation), COX5A (Co-fractionation)

ESM2 similar proteins: A1Z897, A8P488, A8XYZ2, B0VYX1, B0VYX2, B0VYX3, B0VYX4, B0VYX5, B0VYX6, B0VYX7, B0VYX8, B0VYX9, B0VYY0, B0VYY1, B0VYY2, B0VYY3, B0VYY4, B0VYY5, B0XK69, B3MI37, B3N6D9, B4GG58, B4HMQ1, B4KN44, B4KPG8, B4LKE5, B4N665, B4NXN5, B4QID8, B5E0U2, P00426, P00428, P11240, P12787, P19511, P20674, P55954, Q178L7, Q53CF8, Q53CG1

Diamond homologs: B0VYX1, B0VYX2, B0VYX3, B0VYX4, B0VYX5, B0VYX6, B0VYX7, B0VYX8, B0VYX9, B0VYY0, B0VYY1, B0VYY2, B0VYY3, B0VYY4, B0VYY5, O61694, P00426, P00427, P11240, P12787, P20674, P55954, P80972, P80973, Q01359, Q53CF8, Q53CG1, Q94514, Q9UTF6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
COX5A	“form complex”	“Cytochrome c oxidase-Mitochondrial respiratory chain complex IV”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 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
Complex IV assembly	13	31.2×	7e-14
Cytoprotection by HMOX1	10	19.4×	2e-08
Respiratory electron transport	15	15.0×	1e-11
TP53 Regulates Metabolic Genes	9	12.3×	7e-06
Mitochondrial protein degradation	9	10.8×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, cytochrome c to oxygen	9	56.5×	2e-11
cellular respiration	7	24.8×	6e-06
mitochondrial electron transport, NADH to ubiquinone	6	17.6×	4e-04
aerobic respiration	6	12.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	24
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3028911	NM_004255.4(COX5A):c.266T>G (p.Ile89Ser)	Pathogenic
977933	NM_004255.4(COX5A):c.319C>T (p.Arg107Cys)	Pathogenic

SpliceAI

791 predictions. Top by Δscore:

Variant	Effect	Δscore
15:74920438:CCCAT:C	acceptor_gain	1.0000
15:74920439:CCAT:C	acceptor_gain	1.0000
15:74920439:CCATC:C	acceptor_gain	1.0000
15:74920440:CAT:C	acceptor_gain	1.0000
15:74920440:CATC:C	acceptor_gain	1.0000
15:74920442:TCT:T	acceptor_loss	1.0000
15:74920443:C:CA	acceptor_loss	1.0000
15:74920443:C:CC	acceptor_gain	1.0000
15:74920444:T:A	acceptor_loss	1.0000
15:74923646:AC:A	donor_gain	1.0000
15:74923647:CC:C	donor_gain	1.0000
15:74923770:CCTG:C	acceptor_loss	1.0000
15:74923771:C:CC	acceptor_gain	1.0000
15:74926761:CTGA:C	donor_loss	1.0000
15:74926762:TGACC:T	donor_loss	1.0000
15:74926763:GACCT:G	donor_loss	1.0000
15:74926765:C:G	donor_loss	1.0000
15:74926885:TCC:T	acceptor_gain	1.0000
15:74926886:CCC:C	acceptor_gain	1.0000
15:74929115:CCT:C	donor_gain	1.0000
15:74929233:C:CC	acceptor_gain	1.0000
15:74920441:AT:A	acceptor_gain	0.9900
15:74923641:CGCTT:C	donor_loss	0.9900
15:74923643:CTTA:C	donor_loss	0.9900
15:74923644:TTACC:T	donor_loss	0.9900
15:74923645:T:TA	donor_loss	0.9900
15:74923646:A:AC	donor_gain	0.9900
15:74923647:C:CC	donor_gain	0.9900
15:74923774:A:C	acceptor_gain	0.9900
15:74926768:TAACA:T	donor_gain	0.9900

AlphaMissense

955 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:74923721:A:G	L130P	0.987
15:74929167:A:G	W56R	0.987
15:74929167:A:T	W56R	0.987
15:74926817:G:C	C96W	0.986
15:74926827:A:G	L93S	0.986
15:74926770:A:T	V112D	0.984
15:74929116:C:G	G73R	0.984
15:74929116:C:T	G73R	0.984
15:74929154:A:G	F60S	0.984
15:74923765:T:A	K115N	0.983
15:74923765:T:G	K115N	0.983
15:74926788:A:T	V106D	0.983
15:74926830:G:T	A92D	0.983
15:74929129:C:A	W68C	0.983
15:74929129:C:G	W68C	0.983
15:74929165:C:A	W56C	0.982
15:74929165:C:G	W56C	0.982
15:74923721:A:T	L130H	0.981
15:74926785:C:G	R107P	0.981
15:74923733:A:T	V126D	0.980
15:74929116:C:A	G73W	0.980
15:74926814:T:A	R97S	0.979
15:74926814:T:G	R97S	0.979
15:74926815:C:G	R97T	0.979
15:74923709:A:G	L134S	0.978
15:74926834:C:G	A91P	0.977
15:74926857:A:T	V83D	0.977
15:74929131:A:G	W68R	0.977
15:74929131:A:T	W68R	0.977
15:74926818:C:T	C96Y	0.976

dbSNP variants (sampled 300 via entrez): RS1000058711 (15:74933697 A>G), RS1000101425 (15:74926271 A>C), RS1000211607 (15:74922310 C>T), RS1000242851 (15:74922043 T>C), RS1000531178 (15:74921111 G>A), RS1000645674 (15:74920858 G>C), RS1000728707 (15:74937956 C>G,T), RS1000762032 (15:74927330 C>A,G,T), RS1000903685 (15:74934238 C>G,T), RS1001132086 (15:74927608 A>C), RS1001420854 (15:74921885 T>C), RS1001492098 (15:74930116 A>T), RS1001529152 (15:74921598 T>G), RS1001630724 (15:74927995 T>C), RS1001727875 (15:74934800 C>G)

Disease associations

OMIM: gene MIM:603773 | disease phenotypes: MIM:619064

GenCC curated gene-disease

Disease	Classification	Inheritance
cytochrome-c oxidase deficiency disease	Supportive	Autosomal recessive
mitochondrial complex IV deficiency, nuclear type 20	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (2): mitochondrial complex IV deficiency, nuclear type 20 (MONDO:0033655), (MONDO:0009068)

Orphanet (0):

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000260	Wide anterior fontanel
HP:0000490	Deeply set eye
HP:0000527	Long eyelashes
HP:0000664	Synophrys
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001348	Brisk reflexes
HP:0001522	Death in infancy
HP:0001531	Failure to thrive in infancy
HP:0001640	Cardiomegaly
HP:0002007	Frontal bossing
HP:0002092	Pulmonary arterial hypertension
HP:0002151	Increased circulating lactate concentration
HP:0002240	Hepatomegaly
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003348	Hyperalaninemia
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003819	Death in childhood
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0008358	Hyperprolinemia

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001032_3	Caffeine consumption	6.000000e-07
GCST006167_68	Mean arterial pressure x alcohol consumption interaction (2df test)	4.000000e-13
GCST006169_9	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	3.000000e-13
GCST006170_11	Systolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	1.000000e-11
GCST006170_37	Systolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	4.000000e-12
GCST006190_13	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-16
GCST006190_83	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	7.000000e-25
GCST006192_57	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-18
GCST006192_84	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-13
GCST006193_46	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-18
GCST006193_84	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-27
GCST006195_35	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-15
GCST006195_76	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-20
GCST006434_45	Systolic blood pressure x alcohol consumption interaction (2df test)	6.000000e-16
GCST011365_4	Myocardial infarction	4.000000e-08
GCST90002399_368	Neutrophil percentage of white cells	4.000000e-18

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004330	coffee consumption
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0006527	smoking status measurement
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066457 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.44	Kd	3623	nM	CHEMBL3752910
5.44	ED50	3623	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148129: Binding affinity to human COX5A incubated for 45 mins by Kinobead based pull down assay	kd	3.6233	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Doxorubicin	affects response to substance, affects expression	2
Rotenone	increases expression	2
Particulate Matter	increases abundance, decreases expression	2
methylmercuric chloride	decreases expression	1
bisphenol A	affects expression	1
nobiletin	decreases reaction, decreases expression	1
sodium arsenate	decreases expression, decreases reaction	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
gossypol acetic acid	decreases expression	1
pinosylvin	decreases expression	1
microcystin RR	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	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
dibutyldi(4-chlorobenzohydroxamato)tin(IV)	decreases expression	1
bisphenol S	decreases methylation	1
LDN 193189	decreases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects response to substance, affects abundance	1
Arsenicals	affects abundance, affects response to substance	1
Atrazine	decreases expression	1
Capsaicin	increases expression	1
Copper	affects binding, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651171	Binding	Binding affinity to human COX5A incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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