COX6A2

Summary

COX6A2 (cytochrome c oxidase subunit 6A2, HGNC:2279) is a protein-coding gene on chromosome 16p11.2, encoding Cytochrome c oxidase subunit 6A2, mitochondrial (Q02221). Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes polypeptide 2 (heart/muscle isoform) of subunit VIa, and polypeptide 2 is present only in striated muscles. Polypeptide 1 (liver isoform) of subunit VIa is encoded by a different gene, and is found in all non-muscle tissues. These two polypeptides share 66% amino acid sequence identity.

Source: NCBI Gene 1339 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Moderate, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 29 total — 1 likely-pathogenic
• Phenotypes (HPO): 13
• MANE Select transcript: NM_005205

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2279
Approved symbol	COX6A2
Name	cytochrome c oxidase subunit 6A2
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	COX6AH, COXVIAH, COXVIa-M
Ensembl gene	ENSG00000156885
Ensembl biotype	protein_coding
OMIM	602009
Entrez	1339

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000287490, ENST00000565462, ENST00000943485

RefSeq mRNA: 1 — MANE Select: NM_005205 NM_005205

CCDS: CCDS10712

Canonical transcript exons

ENST00000287490 — 3 exons

Exon	Start	End
ENSE00001028899	31427731	31427857
ENSE00001028900	31428015	31428151
ENSE00001028901	31428253	31428360

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 99.92.

FANTOM5 (CAGE): breadth broad, TPM avg 63.0694 / max 10496.3435, expressed in 244 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157157	56.3335	217
157158	3.9850	104
157159	2.4029	92
157156	0.1783	34
157155	0.1697	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.92	gold quality
apex of heart	UBERON:0002098	99.91	gold quality
gastrocnemius	UBERON:0001388	99.83	gold quality
right atrium auricular region	UBERON:0006631	99.79	gold quality
triceps brachii	UBERON:0001509	99.55	gold quality
cardiac atrium	UBERON:0002081	99.55	gold quality
heart left ventricle	UBERON:0002084	99.55	gold quality
cardiac ventricle	UBERON:0002082	99.50	gold quality
gluteal muscle	UBERON:0002000	99.32	gold quality
diaphragm	UBERON:0001103	99.24	gold quality
biceps brachii	UBERON:0001507	99.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.09	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.03	gold quality
left ventricle myocardium	UBERON:0006566	98.95	gold quality
heart right ventricle	UBERON:0002080	98.68	gold quality
skeletal muscle tissue	UBERON:0001134	98.61	gold quality
quadriceps femoris	UBERON:0001377	98.61	gold quality
tibialis anterior	UBERON:0001385	98.60	gold quality
body of tongue	UBERON:0011876	98.55	gold quality
vastus lateralis	UBERON:0001379	98.47	gold quality
myocardium	UBERON:0002349	98.03	gold quality
muscle organ	UBERON:0001630	97.90	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.61	gold quality
muscle of leg	UBERON:0001383	97.60	gold quality
heart	UBERON:0000948	95.98	gold quality
deltoid	UBERON:0001476	93.95	gold quality
muscle tissue	UBERON:0002385	93.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.57	gold quality
tongue	UBERON:0001723	87.66	gold quality
right lobe of liver	UBERON:0001114	84.99	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.82
E-MTAB-5061	no	3.12

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 4)

• Bi-allelic variants in COX6A2 cause a striated muscle-specific form of COX deficiency. (PMID:31155743)
• Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function. (PMID:32744742)
• Mitochondrial, exosomal miR137-COX6A2 and gamma synchrony as biomarkers of parvalbumin interneurons, psychopathology, and neurocognition in schizophrenia. (PMID:34686767)
• COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes. (PMID:38072986)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cox6a1	ENSDARG00000022438
mus_musculus	Cox6a2	ENSMUSG00000030785
rattus_norvegicus	Cox6a2	ENSRNOG00000019851
drosophila_melanogaster	levy	FBGN0034877
drosophila_melanogaster	COX6AL2	FBGN0036830
drosophila_melanogaster	COX6AL	FBGN0050093
caenorhabditis_elegans		WBGENE00006519

Paralogs (1): COX6A1 (ENSG00000111775)

Protein

Protein identifiers

Cytochrome c oxidase subunit 6A2, mitochondrial — Q02221 (reviewed: Q02221)

Alternative names: Cytochrome c oxidase polypeptide VIa-heart, Cytochrome c oxidase subunit VIA-muscle

All UniProt accessions (1): Q02221

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 unsing 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix. Plays a role in the assembly and stabilization of complex IV.

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)).

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Expressed specifically in heart and muscle. Not detected in brain, colon, spleen, kidney, liver, lung and pancreas.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 18 (MC4DN18) [MIM:619062] An autosomal recessive, muscle-specific, mitochondrial disorder with onset in infancy. MC4DN18 is characterized by hypotonia, limb and facial muscle weakness, and high arched palate. Some patients have respiratory insufficiency at birth and cardiomyopathy. Patient skeletal muscle shows decreased levels and activity of mitochondrial respiratory complex IV. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Energy metabolism; oxidative phosphorylation.

Similarity. Belongs to the cytochrome c oxidase subunit 6A family.

RefSeq proteins (1): NP_005196* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001349	Cyt_c_oxidase_su6a	Family
IPR018507	Cyt_c_oxidase_su6a_CS	Conserved_site
IPR036418	Cyt_c_oxidase_su6a_sf	Homologous_superfamily

Pfam: PF02046

UniProt features (8 total): topological domain 2, sequence variant 2, transit peptide 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02221-F1	87.30	0.72

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

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

MSigDB gene sets: 188 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, MORF_MSH3, MORF_BRCA1, MORF_ATRX, HUMMERICH_BENIGN_SKIN_TUMOR_DN, HUMMERICH_MALIGNANT_SKIN_TUMOR_DN, MORF_ESR1, CAGCTG_AP4_Q5, GNF2_MYL3, MORF_RAD51L3, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_OXIDATIVE_PHOSPHORYLATION, chr16p11, GOBP_ELECTRON_TRANSPORT_CHAIN, KEGG_HUNTINGTONS_DISEASE

GO Biological Process (3): generation of precursor metabolites and energy (GO:0006091), mitochondrial electron transport, cytochrome c to oxygen (GO:0006123), oxidative phosphorylation (GO:0006119)

GO Molecular Function (2): oxidoreductase activity (GO:0016491), enzyme regulator activity (GO:0030234)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex IV (GO:0045277), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	2
metabolic process	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
aerobic respiration	1
proton motive force-driven ATP synthesis	1
molecular function regulator activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial 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

1577 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX6A2	COX6B1	P14854	957
COX6A2	COX5B	P10606	924
COX6A2	COX5A	P20674	911
COX6A2	COX7A1	P24310	886
COX6A2	COX6C	P09669	884
COX6A2	COXFA4	O00483	853
COX6A2	COX7C	P15954	810
COX6A2	COX4I1	P13073	801
COX6A2	COX7B	P24311	794
COX6A2	COX4I2	Q96KJ9	788
COX6A2	COX8A	P10176	730
COX6A2	COX15	Q7KZN9	623
COX6A2	PTGS1	P23219	617
COX6A2	COX7A2	P14406	615
COX6A2	COX6B2	Q6YFQ2	608

IntAct

8 interactions, top by confidence:

A	B	Type	Score
COA3	MT-CO1	psi-mi:“MI:0914”(association)	0.610
COL6A2	COX6A2	psi-mi:“MI:0915”(physical association)	0.370
MRPL12	COX6A2	psi-mi:“MI:0915”(physical association)	0.370
COX6A2	POT1	psi-mi:“MI:0915”(physical association)	0.370
SNX21	COX6A2	psi-mi:“MI:0915”(physical association)	0.370
COX6C	NDUFB8	psi-mi:“MI:0914”(association)	0.350
COX6A2	MT-CO1	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): APP (Reconstituted Complex), SNX21 (Two-hybrid), COX6A2 (Two-hybrid), MRPL12 (Two-hybrid), POT1 (Two-hybrid)

ESM2 similar proteins: O13082, O13085, O46577, O46578, O46579, O46580, O46581, O46584, O46585, O46586, O64725, P00423, P06810, P07471, P10817, P10818, P10888, P12074, P13073, P13183, P19783, P24311, P32799, P43023, P43024, P56393, P80431, P80971, Q02221, Q08CE7, Q0MQC7, Q20779, Q28ED6, Q4R648, Q5R9K2, Q5RC38, Q5RK28, Q5XG64, Q810Q5, Q8TF08

Diamond homologs: O13082, O13085, O74471, P07471, P10817, P10818, P12074, P13182, P32799, P43023, P43024, Q02221, Q20779, Q5RC38, Q9TTT7, V5IRD7, P61902, P61903, Q9T070

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	23
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
638271	NM_005205.4(COX6A2):c.117C>A (p.Ser39Arg)	Likely pathogenic

SpliceAI

145 predictions. Top by Δscore:

Variant	Effect	Δscore
16:31428010:CGTA:C	donor_loss	1.0000
16:31428011:GTAC:G	donor_loss	1.0000
16:31428012:TACC:T	donor_loss	1.0000
16:31428014:C:CG	donor_loss	1.0000
16:31427853:TAGGG:T	acceptor_gain	0.9900
16:31427855:GGG:G	acceptor_gain	0.9900
16:31427856:GG:G	acceptor_gain	0.9900
16:31427858:C:CC	acceptor_gain	0.9900
16:31427870:C:CT	acceptor_gain	0.9900
16:31427871:G:T	acceptor_gain	0.9900
16:31428013:A:AC	donor_gain	0.9900
16:31428013:AC:A	donor_gain	0.9900
16:31428014:C:CC	donor_gain	0.9900
16:31428014:CC:C	donor_gain	0.9900
16:31428254:T:TA	donor_gain	0.9900
16:31427854:AGGG:A	acceptor_gain	0.9800
16:31427857:GC:G	acceptor_loss	0.9800
16:31427858:C:CA	acceptor_loss	0.9800
16:31427860:G:C	acceptor_gain	0.9800
16:31428148:CGAG:C	acceptor_gain	0.9800
16:31428251:ACCT:A	donor_gain	0.9800
16:31428252:CCTC:C	donor_gain	0.9800
16:31428272:T:TA	donor_gain	0.9800
16:31428248:CTCA:C	donor_loss	0.9700
16:31428249:TCA:T	donor_loss	0.9700
16:31428250:CACCT:C	donor_loss	0.9700
16:31428014:CCT:C	donor_gain	0.9600
16:31428014:CCTTG:C	donor_gain	0.9400
16:31428152:C:CC	acceptor_gain	0.9400
16:31428252:CCT:C	donor_gain	0.9300

AlphaMissense

612 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:31428048:G:C	F59L	0.993
16:31428048:G:T	F59L	0.993
16:31428050:A:G	F59L	0.993
16:31428108:G:C	S39R	0.990
16:31428108:G:T	S39R	0.990
16:31428110:T:G	S39R	0.990
16:31427804:G:C	N88K	0.986
16:31427804:G:T	N88K	0.986
16:31428118:G:T	A36E	0.983
16:31428022:C:G	R68P	0.982
16:31427821:G:C	H83D	0.981
16:31428103:G:T	A41D	0.978
16:31427838:C:A	G77V	0.975
16:31428023:G:T	R68S	0.973
16:31428098:A:G	C43R	0.972
16:31427829:G:A	T80I	0.971
16:31428049:A:G	F59S	0.969
16:31427848:A:G	W74R	0.967
16:31427848:A:T	W74R	0.967
16:31428049:A:C	F59C	0.967
16:31428112:G:C	P38R	0.964
16:31427819:G:C	H83Q	0.961
16:31427819:G:T	H83Q	0.961
16:31428112:G:T	P38H	0.959
16:31427823:A:G	F82S	0.958
16:31428031:A:T	L65H	0.958
16:31428028:C:G	R66P	0.956
16:31428143:A:G	W28R	0.956
16:31428143:A:T	W28R	0.956
16:31427821:G:T	H83N	0.955

dbSNP variants (sampled 300 via entrez): RS1000630589 (16:31429958 A>G), RS1001390326 (16:31429241 C>G,T), RS1002278435 (16:31428922 G>A), RS1002300977 (16:31428388 C>T), RS1004741423 (16:31430309 G>A,T), RS1005198220 (16:31427677 G>A,C,T), RS1005899763 (16:31427712 T>A,C,G), RS1006204177 (16:31429064 G>A), RS1007193996 (16:31428410 C>A,T), RS1007962166 (16:31429167 C>G,T), RS1009427334 (16:31428150 A>C,G), RS1010419674 (16:31430202 G>C), RS1011883042 (16:31430287 G>A), RS1012366461 (16:31429996 A>G), RS1013626331 (16:31428522 G>T)

Disease associations

OMIM: gene MIM:602009 | disease phenotypes: MIM:619062

GenCC curated gene-disease

Disease	Classification	Inheritance
cytochrome-c oxidase deficiency disease	Supportive	Autosomal recessive
mitochondrial complex IV deficiency, nuclear type 18	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 18 (MONDO:0033653), (MONDO:0009068)

Orphanet (0):

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0002151	Increased circulating lactate concentration
HP:0002643	Neonatal respiratory distress
HP:0003542	Increased circulating pyruvate concentration
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003688	Cytochrome C oxidase-negative muscle fibers
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0012240	Increased intramyocellular lipid droplets
HP:0030319	Weakness of facial musculature

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	2
Aflatoxin B1	decreases methylation, decreases expression	2
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
incobotulinumtoxinA	decreases expression	1
Rosiglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Azacitidine	increases expression	1
Carmustine	decreases expression	1
Bucladesine	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Etoposide	decreases expression	1
Lipopolysaccharides	decreases expression	1
Triclosan	decreases expression	1
Cyclosporine	decreases expression	1
Medroxyprogesterone Acetate	affects cotreatment, increases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4UB	WAe009-A-47	Embryonic stem cell	Female

Clinical trials (associated diseases)

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