COX14

Summary

COX14 (cytochrome c oxidase assembly factor COX14, HGNC:28216) is a protein-coding gene on chromosome 12q13.12, encoding Cytochrome c oxidase assembly protein COX14 (Q96I36). Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.

This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase (COX; also known as complex IV) subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 84987 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cytochrome-c oxidase deficiency disease (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 49 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• MANE Select transcript: NM_032901

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28216
Approved symbol	COX14
Name	cytochrome c oxidase assembly factor COX14
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	MGC14288
Ensembl gene	ENSG00000178449
Ensembl biotype	protein_coding
OMIM	614478
Entrez	84987

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000317943, ENST00000548985, ENST00000550487, ENST00000550654, ENST00000962517, ENST00000962518

RefSeq mRNA: 3 — MANE Select: NM_032901 NM_001257133, NM_001257134, NM_032901

CCDS: CCDS8800

Canonical transcript exons

ENST00000550487 — 2 exons

Exon	Start	End
ENSE00002384999	50112236	50112301
ENSE00003844920	50120036	50120453

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.8964 / max 225.3303, expressed in 1821 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125422	35.3710	1820
125420	0.5254	266

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.04	gold quality
right atrium auricular region	UBERON:0006631	98.84	gold quality
cardiac atrium	UBERON:0002081	98.74	gold quality
heart left ventricle	UBERON:0002084	98.71	gold quality
cardiac ventricle	UBERON:0002082	98.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.56	gold quality
right adrenal gland	UBERON:0001233	98.52	gold quality
kidney epithelium	UBERON:0004819	98.48	gold quality
heart	UBERON:0000948	98.46	gold quality
gastrocnemius	UBERON:0001388	98.46	gold quality
adenohypophysis	UBERON:0002196	98.45	gold quality
left adrenal gland	UBERON:0001234	98.44	gold quality
mucosa of transverse colon	UBERON:0004991	98.42	gold quality
left adrenal gland cortex	UBERON:0035825	98.38	gold quality
right adrenal gland cortex	UBERON:0035827	98.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.24	gold quality
muscle of leg	UBERON:0001383	98.23	gold quality
lower esophagus	UBERON:0013473	98.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.19	gold quality
left ventricle myocardium	UBERON:0006566	98.17	gold quality
islet of Langerhans	UBERON:0000006	98.15	gold quality
omental fat pad	UBERON:0010414	98.14	gold quality
left coronary artery	UBERON:0001626	98.13	gold quality
peritoneum	UBERON:0002358	98.12	gold quality
pituitary gland	UBERON:0000007	98.09	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.08	gold quality
adrenal cortex	UBERON:0001235	98.06	gold quality
right lobe of thyroid gland	UBERON:0001119	98.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.01	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	23.56
E-MTAB-2983	no	407.44
E-GEOD-83139	no	3.87
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting COX14, 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-545-3P	99.95	70.74	2783
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-654-3P	98.38	67.61	905
HSA-MIR-619-3P	98.38	65.58	693
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-3661	97.83	67.30	705
HSA-MIR-6865-3P	97.54	64.67	684
HSA-MIR-631	97.05	66.93	602

Literature-anchored findings (GeneRIF, showing 2)

• While PCAG1 mRNA was highly expressed in prostate cancer tissues, it was almost absent in all common normal tissues and paired adjacent normal prostate tissues. (PMID:23292432)
• COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors (PMID:25604084)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cox14	ENSMUSG00000023020
rattus_norvegicus	Cox14	ENSRNOG00000084326

Protein

Protein identifiers

Cytochrome c oxidase assembly protein COX14 — Q96I36 (reviewed: Q96I36)

All UniProt accessions (1): Q96I36

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. Requires for coordination of the early steps of cytochrome c oxidase assembly with the synthesis of MT-CO1.

Subunit / interactions. Along with COA3, core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex.

Subcellular location. Mitochondrion outer membrane.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 10 (MC4DN10) [MIM:619053] An autosomal recessive mitochondrial disorder that manifests with neonatal neurological and respiratory distress. Clinical features include facial dysmorphism, hypotelorism, microphthalmia, an ogival palate, and severe metabolic acidosis. Death occurs in early infancy. Autoptic examination reveals brain hypertrophy, diffuse alteration of white matter myelination, numerous cavities in the parieto-occipital region, brainstem and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal hyperplasia. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. The disease may be caused by variants affecting the gene represented in this entry.

RefSeq proteins (3): NP_001244062, NP_001244063, NP_116290* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029208	COX14	Family

Pfam: PF14880

UniProt features (5 total): topological domain 2, chain 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96I36-F1	86.03	0.51

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 134 (showing top): GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, TGACCTY_ERR1_Q2, SRF_Q5_01, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_PROTEIN_MATURATION, TGCTGAY_UNKNOWN, GOCC_MITOCHONDRIAL_ENVELOPE, TGACATY_UNKNOWN, GOBP_PROTEIN_FOLDING, GOCC_ORGANELLE_INNER_MEMBRANE, MZF1_01, GOCC_ORGANELLE_ENVELOPE, LU_EZH2_TARGETS_UP

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

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

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

Protein interactions and networks

STRING

1084 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX14	COA3	Q9Y2R0	984
COX14	SURF1	Q15526	869
COX14	MSS51	Q4VC12	802
COX14	COA1	Q9GZY4	791
COX14	COX5A	P20674	721
COX14	COA5	Q86WW8	680
COX14	SMIM20	Q8N5G0	675
COX14	TACO1	Q9BSH4	667
COX14	PET100	P0DJ07	661
COX14	CMC1	Q7Z7K0	656
COX14	COX15	Q7KZN9	650
COX14	COX20	Q5RI15	645
COX14	COX10	Q12887	644
COX14	COA6	Q5JTJ3	625
COX14	COX18	Q8N8Q8	625

IntAct

16 interactions, top by confidence:

A	B	Type	Score
COA3	MT-CO1	psi-mi:“MI:0914”(association)	0.610
COA3	MT-CO1	psi-mi:“MI:0915”(physical association)	0.610
	COX14	psi-mi:“MI:0915”(physical association)	0.560
MESD	COX14	psi-mi:“MI:0915”(physical association)	0.560
SPPL2B	GPR89A	psi-mi:“MI:0914”(association)	0.350
COA3	COX5B	psi-mi:“MI:0914”(association)	0.350
COA3	TMEM223	psi-mi:“MI:0914”(association)	0.350
COX14	MT-CO1	psi-mi:“MI:0914”(association)	0.350
SLC25A5	TMEM223	psi-mi:“MI:0914”(association)	0.350
COX14	NUDT19	psi-mi:“MI:2364”(proximity)	0.270
COX14		psi-mi:“MI:0915”(physical association)	0.000
COX14	MESD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (147): COX14 (Two-hybrid), COX17 (Proximity Label-MS), NUDT19 (Proximity Label-MS), HAX1 (Proximity Label-MS), NDUFS8 (Proximity Label-MS), DNM1L (Proximity Label-MS), TXNDC9 (Proximity Label-MS), COPE (Proximity Label-MS), SEC16A (Proximity Label-MS), PGRMC2 (Proximity Label-MS), YKT6 (Proximity Label-MS), TIMM44 (Proximity Label-MS), NDUFA2 (Proximity Label-MS), TRIAP1 (Proximity Label-MS), CALU (Proximity Label-MS)

ESM2 similar proteins: A1L2P2, A1XQR7, A8E7D3, A8MTT3, L0R6Q1, O48832, O64497, O82803, P11951, P13183, P14790, P24311, P43883, P46270, P80977, Q148H0, Q1LUK1, Q1MTD4, Q1RMH3, Q21154, Q28EM2, Q2ACH7, Q41112, Q4V8S3, Q5BKW8, Q5CZQ0, Q5R987, Q5XFV8, Q5XKP0, Q63ZZ0, Q68EV8, Q7SGT7, Q7YRK0, Q7YRK1, Q810Q5, Q84K90, Q8BH51, Q8BTE5, Q8R404, Q8VCR3

Diamond homologs: A8E7D3, Q1RMH3, Q5XFV8, Q8BH51, Q96I36

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
COX14	“form complex”	“MITRAC complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	24
Likely benign	14
Benign	5

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
31196	NM_032901.4(COX14):c.57G>A (p.Met19Ile)	Pathogenic
214250	NM_032901.4(COX14):c.81dup (p.Tyr28fs)	Likely pathogenic

SpliceAI

542 predictions. Top by Δscore:

Variant	Effect	Δscore
12:50112298:CCAG:C	donor_loss	0.9800
12:50112299:CAGGT:C	donor_loss	0.9800
12:50112300:AG:A	donor_loss	0.9800
12:50112301:GGT:G	donor_loss	0.9800
12:50112775:C:G	donor_gain	0.9800
12:50120034:AG:A	acceptor_gain	0.9800
12:50120035:GG:G	acceptor_gain	0.9800
12:50112302:GT:G	donor_loss	0.9700
12:50112303:T:G	donor_loss	0.9700
12:50120030:TTGTA:T	acceptor_loss	0.9700
12:50120031:TGTA:T	acceptor_loss	0.9700
12:50120032:GTA:G	acceptor_loss	0.9700
12:50120033:TAGGG:T	acceptor_loss	0.9700
12:50120034:A:AG	acceptor_gain	0.9700
12:50120035:G:GC	acceptor_loss	0.9700
12:50120035:G:GG	acceptor_gain	0.9700
12:50112084:C:T	donor_gain	0.9600
12:50112687:G:GT	donor_gain	0.9600
12:50120034:AGG:A	acceptor_gain	0.9600
12:50120035:GGG:G	acceptor_gain	0.9600
12:50112688:A:T	donor_gain	0.9400
12:50112494:G:GG	donor_gain	0.9300
12:50112491:GCA:G	donor_gain	0.9200
12:50112904:G:GG	donor_gain	0.9200
12:50112901:GAT:G	donor_gain	0.9100
12:50113188:C:CG	donor_gain	0.9100
12:50112909:T:G	donor_gain	0.8900
12:50112444:C:CA	acceptor_gain	0.8800
12:50112731:G:GT	donor_gain	0.8800
12:50120025:T:A	acceptor_loss	0.8800

AlphaMissense

364 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:50120082:G:C	K13N	0.892
12:50120082:G:T	K13N	0.892
12:50120086:T:C	F15L	0.888
12:50120088:C:A	F15L	0.888
12:50120088:C:G	F15L	0.888
12:50120134:A:C	S31R	0.865
12:50120136:T:A	S31R	0.865
12:50120136:T:G	S31R	0.865
12:50120075:G:A	G11D	0.848
12:50120100:G:A	M19I	0.822
12:50120100:G:C	M19I	0.822
12:50120100:G:T	M19I	0.822
12:50120122:G:A	G27R	0.815
12:50120122:G:C	G27R	0.815
12:50120058:G:C	K5N	0.800
12:50120058:G:T	K5N	0.800
12:50120123:G:A	G27E	0.783
12:50120105:T:A	L21H	0.782
12:50120108:T:A	L22H	0.766
12:50120131:T:C	C30R	0.765
12:50120074:G:C	G11R	0.764
12:50120096:C:A	S18Y	0.723
12:50120105:T:G	L21R	0.715
12:50120114:T:A	V24E	0.712
12:50120125:T:G	Y28D	0.709
12:50120077:T:C	Y12H	0.679
12:50120077:T:G	Y12D	0.676
12:50120102:T:G	M20R	0.675
12:50120108:T:G	L22R	0.675
12:50120080:A:G	K13E	0.664

dbSNP variants (sampled 300 via entrez): RS1000506819 (12:50120688 A>G), RS1000536565 (12:50116781 C>G), RS1000714462 (12:50114226 A>AAC), RS1001021106 (12:50111290 A>C,G), RS1001091099 (12:50110927 G>A), RS1001360995 (12:50112482 C>T), RS1001533702 (12:50113491 G>A), RS1001541919 (12:50113740 C>G,T), RS1002322750 (12:50118343 G>A), RS1002554814 (12:50113024 T>A,G), RS1002559071 (12:50120465 G>A), RS1002575491 (12:50118648 T>A), RS1002710764 (12:50117216 A>G), RS1003068036 (12:50119810 G>C), RS1003191619 (12:50112195 T>A)

Disease associations

OMIM: gene MIM:614478 | disease phenotypes: MIM:619053

GenCC curated gene-disease

Disease	Classification	Inheritance
cytochrome-c oxidase deficiency disease	Supportive	Autosomal recessive
mitochondrial complex IV deficiency, nuclear type 10	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Limited	AR

Mondo (2): mitochondrial complex IV deficiency, nuclear type 10 (MONDO:0033639), (MONDO:0009068)

Orphanet (0):

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000089	Renal hypoplasia
HP:0000218	High palate
HP:0000568	Microphthalmia
HP:0000601	Hypotelorism
HP:0000954	Single transverse palmar crease
HP:0001562	Oligohydramnios
HP:0001639	Hypertrophic cardiomyopathy
HP:0001942	Metabolic acidosis
HP:0002151	Increased circulating lactate concentration
HP:0002240	Hepatomegaly
HP:0002490	Increased CSF lactate
HP:0002643	Neonatal respiratory distress
HP:0002919	Ketonuria
HP:0011400	Abnormal CNS myelination

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST007094_175	Diastolic blood pressure	4.000000e-14
GCST007095_15	Systolic blood pressure	3.000000e-07
GCST007095_16	Systolic blood pressure	2.000000e-06
GCST007098_67	Diastolic blood pressure	7.000000e-10
GCST007098_68	Diastolic blood pressure	2.000000e-09
GCST007099_131	Systolic blood pressure	1.000000e-10
GCST007267_311	Systolic blood pressure	3.000000e-17
GCST007293_76	Body fat distribution (arm fat ratio)	4.000000e-07
GCST007294_123	Body fat distribution (trunk fat ratio)	2.000000e-09
GCST007294_2	Body fat distribution (trunk fat ratio)	1.000000e-18
GCST007295_152	Body fat distribution (leg fat ratio)	4.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0004341	body fat distribution

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067421 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.30	Kd	4.956	nM	CHEMBL3752910
8.30	ED50	4.956	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 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	2149842: Binding affinity to human COX14 incubated for 45 mins by Kinobead based pull down assay	kd	0.0050	uM

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, decreases expression, increases expression	4
Valproic Acid	affects expression, increases expression	3
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
sodium arsenite	decreases expression	1
K 7174	decreases expression	1
Acetaminophen	decreases expression	1
Cisplatin	increases expression	1
Diazinon	increases methylation	1
Doxorubicin	increases expression	1
Fluorouracil	affects expression	1
Cyclosporine	decreases expression	1
Sodium Selenite	increases expression	1
Copper Sulfate	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
CHEMBL5652884	Binding	Binding affinity to human COX14 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.