COX16

Summary

COX16 (cytochrome c oxidase assembly factor COX16, HGNC:20213) is a protein-coding gene on chromosome 14q24.2, encoding Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (Q9P0S2). Required for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase.

Involved in mitochondrial cytochrome c oxidase assembly. Located in mitochondrial inner membrane. Implicated in mitochondrial complex IV deficiency nuclear type 22.

Source: NCBI Gene 51241 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial complex IV deficiency, nuclear type 22 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 17 total — 1 pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_016468

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20213
Approved symbol	COX16
Name	cytochrome c oxidase assembly factor COX16
Location	14q24.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPC203
Ensembl gene	ENSG00000133983
Ensembl biotype	protein_coding
OMIM	618064
Entrez	51241

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000389912, ENST00000554366, ENST00000555276, ENST00000555601, ENST00000557612, ENST00000854462, ENST00000854463, ENST00000854464, ENST00000854465, ENST00000854466, ENST00000940438

RefSeq mRNA: 2 — MANE Select: NM_016468 NM_001204090, NM_016468

CCDS: CCDS9802

Canonical transcript exons

ENST00000389912 — 4 exons

Exon	Start	End
ENSE00001518100	70325081	70326449
ENSE00001518105	70359519	70359683
ENSE00003487573	70342658	70342729
ENSE00003570828	70329174	70329236

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 97.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 90.1445 / max 1789.2835, expressed in 1820 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143912	84.7486	1819
143913	3.0513	1399
143911	2.3446	1259
143915	0.2570	124

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.14	gold quality
ventricular zone	UBERON:0003053	96.52	gold quality
calcaneal tendon	UBERON:0003701	96.47	gold quality
body of pancreas	UBERON:0001150	96.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.43	gold quality
cortical plate	UBERON:0005343	96.03	gold quality
mucosa of transverse colon	UBERON:0004991	95.86	gold quality
islet of Langerhans	UBERON:0000006	95.79	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.78	gold quality
adrenal tissue	UBERON:0018303	95.63	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.59	gold quality
rectum	UBERON:0001052	95.33	gold quality
right adrenal gland	UBERON:0001233	95.22	gold quality
right adrenal gland cortex	UBERON:0035827	95.15	gold quality
pancreas	UBERON:0001264	95.07	gold quality
gastrocnemius	UBERON:0001388	94.89	gold quality
muscle of leg	UBERON:0001383	94.87	gold quality
right lobe of liver	UBERON:0001114	94.79	gold quality
left adrenal gland	UBERON:0001234	94.78	gold quality
left adrenal gland cortex	UBERON:0035825	94.74	gold quality
gall bladder	UBERON:0002110	94.57	gold quality
body of stomach	UBERON:0001161	94.53	gold quality
anterior cingulate cortex	UBERON:0009835	94.22	gold quality
right atrium auricular region	UBERON:0006631	94.17	gold quality
adrenal gland	UBERON:0002369	94.16	gold quality
lower esophagus mucosa	UBERON:0035834	94.15	gold quality
cingulate cortex	UBERON:0003027	94.12	gold quality
apex of heart	UBERON:0002098	94.03	gold quality
adenohypophysis	UBERON:0002196	94.00	gold quality
skin of abdomen	UBERON:0001416	93.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting COX16, 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-5692A	100.00	74.40	6850
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3910	99.95	71.13	2227
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-153-5P	99.89	73.86	6317
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4677-3P	99.49	67.91	1246

Literature-anchored findings (GeneRIF, showing 2)

• COX16 is required for assembly of cytochrome C oxidase in human cells and is involved in copper delivery to COX2. (PMID:29355485)
• Here, the authors find that COX16, a protein required for cytochrome c oxidase assembly, interacts specifically with newly synthesized COX2 and its copper center-forming metallochaperones SCO1, SCO2, and COA6. The recruitment of SCO1 to the COX2-module is COX16- dependent and patient-mimicking mutations in SCO1 affect interaction with COX16. (PMID:29381136)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cox16	ENSDARG00000039136
mus_musculus	Cox16	ENSMUSG00000091803
rattus_norvegicus	Cox16	ENSRNOG00000047115

Paralogs (2): KIAA1614 (ENSG00000135835), SYNJ2BP (ENSG00000213463)

Protein

Protein identifiers

Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial — Q9P0S2 (reviewed: Q9P0S2)

All UniProt accessions (2): A0A087WX56, Q9P0S2

UniProt curated annotations — full annotation on UniProt →

Function. Required for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase. Promotes the insertion of copper into the active site of cytochrome c oxidase subunit II (MT-CO2/COX2). Interacts specifically with newly synthesized MT-CO2/COX and its copper center-forming metallochaperones SCO1, SCO2 and COA6. Probably facilitates MT-CO2/COX2 association with the MITRAC assembly intermediate containing MT-CO1/COX1, thereby participating in merging the MT-CO1/COX1 and MT-CO2/COX2 assembly lines.

Subunit / interactions. Associates with the MITRAC complex. Interacts with MT-CO2/COX; specifically interacts with newly synthesized MT-CO2/COX. Interacts with SCO1, SCO2 and COA6.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Widely expressed. Expressed at higher level in skeletal muscle, heart and liver.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 22 (MC4DN22) [MIM:619355] An autosomal recessive mitochondrial disorder characterized by hypertrophic cardiomyopathy, encephalopathy, fatal lactic acidosis, and isolated complex IV deficiency. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. No COX16 mutations have been detected in patients with cytochrome c oxidase (COX) deficiency.

Similarity. Belongs to the COX16 family.

RefSeq proteins (2): NP_001191019, NP_057552* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR020164	Cyt_c_Oxase_assmbl_COX16	Family

Pfam: PF14138

UniProt features (7 total): topological domain 2, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0S2-F1	75.50	0.09

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 253 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, chr14q24, GOCC_MITOCHONDRIAL_ENVELOPE, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, GOCC_ORGANELLE_INNER_MEMBRANE, KRIGE_RESPONSE_TO_TOSEDOSTAT_6HR_DN, GOCC_ORGANELLE_ENVELOPE, GRYDER_PAX3FOXO1_ENHANCERS_KO_DOWN, GSE13522_WT_VS_IFNAR_KO_SKIN_UP, ALKBH3_TARGET_GENES

GO Biological Process (1): mitochondrial respiratory chain complex IV assembly (GO:0033617)

GO Molecular Function (2): molecular_function (GO:0003674), protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
respiratory chain complex IV assembly	1
mitochondrial respiratory chain complex assembly	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1034 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX16	COA6	Q5JTJ3	750
COX16	COA3	Q9Y2R0	746
COX16	COX18	Q8N8Q8	744
COX16	SURF1	Q15526	646
COX16	COX15	Q7KZN9	634
COX16	COX17	Q14061	634
COX16	SCO1	O75880	621
COX16	COX14	Q96I36	583
COX16	COX20	Q5RI15	580
COX16	PET117	Q6UWS5	578
COX16	TMEM177	Q53S58	571
COX16	COA1	Q9GZY4	568
COX16	COX11	Q9Y6N1	559
COX16	SCO2	O43819	523
COX16	PET100	P0DJ07	519

IntAct

20 interactions, top by confidence:

A	B	Type	Score
COX16	FAM25C	psi-mi:“MI:0915”(physical association)	0.560
FAM25C	COX16	psi-mi:“MI:0915”(physical association)	0.560
NYX	LYPLA2	psi-mi:“MI:0914”(association)	0.530
COX16	PDIA5	psi-mi:“MI:0915”(physical association)	0.400
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ERGIC3	TMEM223	psi-mi:“MI:0914”(association)	0.350
FCGR3B	NRP2	psi-mi:“MI:0914”(association)	0.350
CDH23	GTPBP10	psi-mi:“MI:0914”(association)	0.350
GPR12	TLCD2	psi-mi:“MI:0914”(association)	0.350
OPALIN	FAM171A2	psi-mi:“MI:0914”(association)	0.350
S1PR1	TNPO2	psi-mi:“MI:0914”(association)	0.350
TNFRSF9	WFS1	psi-mi:“MI:0914”(association)	0.350
SLC39A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
SV2B	C15orf61	psi-mi:“MI:0914”(association)	0.350
COA3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CASP3	TMEM223	psi-mi:“MI:0914”(association)	0.350
SCO1	HAX1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (36): COX16 (Affinity Capture-MS), COX16 (Affinity Capture-MS), COX16 (Affinity Capture-MS), COX16 (Affinity Capture-MS), COX16 (Affinity Capture-MS), COX16 (Affinity Capture-MS), COX16 (Affinity Capture-MS), COX16 (Affinity Capture-MS), COX16 (Affinity Capture-MS), COX2 (Affinity Capture-Western), FH (Positive Genetic), MAPKAP1 (Negative Genetic), MED23 (Negative Genetic), MRPS14 (Positive Genetic), PGK1 (Negative Genetic)

ESM2 similar proteins: A1L2P2, A2VDV9, A5PJ82, D2H617, D3Z9R8, D4ACP2, E2R5I0, E7EXZ6, F6USH3, G1QDE8, G1S9B8, O00483, O95298, P11951, P14790, P56378, P56379, Q0MQ97, Q0MQ98, Q0MQ99, Q0MQF7, Q0MQF8, Q0MQF9, Q0Q4Z0, Q28EM2, Q28GF4, Q2NKS2, Q4FZG9, Q502E5, Q5BKW8, Q5RCY6, Q5RDZ8, Q5REX0, Q62425, Q68EV8, Q69YU5, Q78IK2, Q78RX3, Q7YRJ8, Q7YRK7

Diamond homologs: A0A1N7SYS3, Q2NKS2, Q5RCY6, Q9CR63, Q9P0S2, A1C8Z3, P0CM84, P0CM85, P47081, Q0UIR3, Q1DME3, Q2PIY2, Q4I8P5, Q52ZA1, Q5ACH7, Q5AXJ9, Q6BY05, Q6CCF6, Q6FW43, Q75FA7, Q7SI11, Q9UTK1, Q6CK73

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	13
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1120203	NM_016468.7(COX16):c.244C>T (p.Arg82Ter)	Pathogenic

SpliceAI

1704 predictions. Top by Δscore:

Variant	Effect	Δscore
14:70326446:TTTT:T	acceptor_gain	1.0000
14:70326448:TTC:T	acceptor_loss	1.0000
14:70326449:TCTAT:T	acceptor_loss	1.0000
14:70326450:C:CA	acceptor_loss	1.0000
14:70326450:C:CC	acceptor_gain	1.0000
14:70326452:A:C	acceptor_gain	1.0000
14:70326459:C:CT	acceptor_gain	1.0000
14:70329169:CGTA:C	donor_loss	1.0000
14:70329169:CGTAC:C	donor_loss	1.0000
14:70329170:GTA:G	donor_loss	1.0000
14:70329170:GTAC:G	donor_loss	1.0000
14:70329232:TCCAT:T	acceptor_gain	1.0000
14:70329233:CCAT:C	acceptor_gain	1.0000
14:70329233:CCATC:C	acceptor_gain	1.0000
14:70329234:CAT:C	acceptor_gain	1.0000
14:70329234:CATC:C	acceptor_gain	1.0000
14:70329234:CATCT:C	acceptor_loss	1.0000
14:70329235:AT:A	acceptor_gain	1.0000
14:70329236:TC:T	acceptor_loss	1.0000
14:70329236:TCTGT:T	acceptor_loss	1.0000
14:70329237:C:CC	acceptor_gain	1.0000
14:70329237:CT:C	acceptor_loss	1.0000
14:70329238:T:A	acceptor_loss	1.0000
14:70329239:G:C	acceptor_gain	1.0000
14:70329239:G:GC	acceptor_gain	1.0000
14:70342656:A:AC	donor_gain	1.0000
14:70342657:C:CC	donor_gain	1.0000
14:70342657:CTTTA:C	donor_gain	1.0000
14:70342661:A:AC	donor_gain	1.0000
14:70342662:C:CC	donor_gain	1.0000

AlphaMissense

696 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:70342704:C:T	G32D	0.992
14:70342716:C:T	G28E	0.990
14:70342713:C:T	G29D	0.988
14:70342691:A:C	F36L	0.986
14:70342691:A:T	F36L	0.986
14:70342693:A:G	F36L	0.986
14:70326420:C:A	W78C	0.985
14:70326420:C:G	W78C	0.985
14:70326422:A:G	W78R	0.985
14:70326422:A:T	W78R	0.985
14:70342714:C:G	G29R	0.985
14:70342692:A:G	F36S	0.983
14:70342717:C:G	G28R	0.982
14:70342717:C:T	G28R	0.982
14:70342701:A:T	L33H	0.979
14:70342719:A:T	V27D	0.977
14:70342686:T:G	Q38P	0.974
14:70342701:A:G	L33P	0.974
14:70359532:C:T	G19E	0.974
14:70342680:C:G	R40P	0.973
14:70342690:A:G	S37P	0.964
14:70342692:A:C	F36C	0.962
14:70342705:C:G	G32R	0.962
14:70342698:C:G	R34P	0.960
14:70326399:C:A	R85S	0.958
14:70326399:C:G	R85S	0.958
14:70359529:A:T	V20D	0.956
14:70326400:C:G	R85T	0.954
14:70326393:C:A	W87C	0.951
14:70326393:C:G	W87C	0.951

dbSNP variants (sampled 300 via entrez): RS1000187847 (14:70331935 G>A), RS1000191632 (14:70352184 T>G), RS1000207560 (14:70335096 A>G), RS1000219204 (14:70351746 T>C), RS1000261281 (14:70355959 G>A), RS1000422862 (14:70346142 T>C), RS1000531074 (14:70339936 C>T), RS1000625564 (14:70327761 T>C), RS1000666530 (14:70327694 C>A,T), RS1000714310 (14:70355716 A>T), RS1000751477 (14:70346319 C>T), RS1000949109 (14:70327989 T>C), RS1001137194 (14:70333620 T>C), RS1001235965 (14:70332590 A>G), RS1001400919 (14:70357228 G>A)

Disease associations

OMIM: gene MIM:618064 | disease phenotypes: MIM:619355

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex IV deficiency, nuclear type 22	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (1): mitochondrial complex IV deficiency, nuclear type 22 (MONDO:0859160)

Orphanet (0):

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001298	Encephalopathy
HP:0001399	Hepatic failure
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001635	Congestive heart failure
HP:0001712	Left ventricular hypertrophy
HP:0001943	Hypoglycemia
HP:0002119	Ventriculomegaly
HP:0002181	Cerebral edema
HP:0002353	EEG abnormality
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002919	Ketonuria
HP:0003215	Dicarboxylic aciduria
HP:0003217	Hyperglutaminemia
HP:0003219	Ethylmalonic aciduria
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003256	Abnormality of the coagulation cascade
HP:0003348	Hyperalaninemia
HP:0003542	Increased circulating pyruvate concentration
HP:0003623	Neonatal onset
HP:0004900	Severe lactic acidosis
HP:0008160	3-hydroxydicarboxylic aciduria
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0008358	Hyperprolinemia
HP:0008527	Congenital sensorineural hearing impairment
HP:0008872	Feeding difficulties in infancy
HP:0011461	Fetal onset
HP:0012402	Increased urine alpha-ketoglutarate concentration
HP:0012444	Brain atrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010243_29	Apolipoprotein B levels	3.000000e-20

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004615	apolipoprotein B measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Tunicamycin	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	affects cotreatment, decreases expression, increases abundance	2
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cupric chloride	affects expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
K 7174	decreases expression	1
ICG 001	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Vorinostat	increases expression	1
Acetaminophen	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Indomethacin	affects cotreatment, increases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment	1
Polycyclic Aromatic Hydrocarbons	decreases expression, increases abundance, affects cotreatment	1
Potassium Dichromate	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Sodium Selenite	increases expression	1

Clinical trials (associated diseases)

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