COX15

Summary

COX15 (cytochrome c oxidase assembly factor COX15, HGNC:2263) is a protein-coding gene on chromosome 10q24.2, encoding Heme A synthase COX15 (Q7KZN9). Catalyzes the second reaction in the biosynthesis of heme A, a prosthetic group of mitochondrial cytochrome c oxidase (CcO). It is a selective cancer dependency (DepMap: 26.3% of cell lines).

Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component 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 function in the regulation and assembly of the complex. This nuclear gene encodes a protein which is not a structural subunit, but may be essential for the biogenesis of COX formation and may function in the hydroxylation of heme O, according to the yeast mutant studies. This protein is predicted to contain 5 transmembrane domains localized in the mitochondrial inner membrane. Alternative splicing of this gene generates two transcript variants diverging in the 3’ region.

Source: NCBI Gene 1355 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 551 total — 20 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 59
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 26.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_078470

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2263
Approved symbol	COX15
Name	cytochrome c oxidase assembly factor COX15
Location	10q24.2
Locus type	gene with protein product
Status	Approved
Aliases	CEMCOX2
Ensembl gene	ENSG00000014919
Ensembl biotype	protein_coding
OMIM	603646
Entrez	1355

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000016171, ENST00000370483, ENST00000497381, ENST00000879790, ENST00000879791

RefSeq mRNA: 10 — MANE Select: NM_078470 NM_001320974, NM_001320975, NM_001320976, NM_001372024, NM_001372025, NM_001372026, NM_001372027, NM_001372028, NM_004376, NM_078470

CCDS: CCDS7481, CCDS7482

Canonical transcript exons

ENST00000016171 — 9 exons

Exon	Start	End
ENSE00000000016	99731960	99732127
ENSE00000719584	99716348	99716461
ENSE00000719603	99720987	99721068
ENSE00000811283	99718346	99718500
ENSE00000811288	99729553	99729734
ENSE00001195070	99710868	99714718
ENSE00003264063	99723956	99724123
ENSE00003320905	99726968	99727154
ENSE00003342377	99727441	99727563

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 93.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.5765 / max 139.8894, expressed in 1796 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110995	12.5765	1796

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
caput epididymis	UBERON:0004358	93.96	gold quality
corpus epididymis	UBERON:0004359	93.30	gold quality
cauda epididymis	UBERON:0004360	92.45	gold quality
right uterine tube	UBERON:0001302	91.90	gold quality
adrenal tissue	UBERON:0018303	91.89	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.50	gold quality
right adrenal gland	UBERON:0001233	90.87	gold quality
right adrenal gland cortex	UBERON:0035827	90.72	gold quality
left adrenal gland	UBERON:0001234	90.51	gold quality
renal medulla	UBERON:0000362	90.26	gold quality
body of tongue	UBERON:0011876	90.23	gold quality
adrenal cortex	UBERON:0001235	90.20	gold quality
left adrenal gland cortex	UBERON:0035825	90.15	gold quality
adrenal gland	UBERON:0002369	90.05	gold quality
vastus lateralis	UBERON:0001379	89.90	gold quality
mammary duct	UBERON:0001765	89.87	gold quality
mucosa of stomach	UBERON:0001199	89.72	gold quality
superior surface of tongue	UBERON:0007371	89.68	gold quality
rectum	UBERON:0001052	89.67	gold quality
biceps brachii	UBERON:0001507	89.62	gold quality
epithelium of mammary gland	UBERON:0003244	89.59	gold quality
tongue	UBERON:0001723	89.56	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.29	gold quality
quadriceps femoris	UBERON:0001377	89.17	gold quality
skeletal muscle tissue	UBERON:0001134	88.96	gold quality
esophagus squamous epithelium	UBERON:0006920	88.65	gold quality
muscle organ	UBERON:0001630	88.60	gold quality
skeletal muscle organ	UBERON:0014892	88.60	gold quality
left ovary	UBERON:0002119	88.56	gold quality
islet of Langerhans	UBERON:0000006	88.48	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

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

120 targeting COX15, 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-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-548AC	99.84	70.77	4351

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 26.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy (PMID:12474143)
• A patient with typical clinical and neuroradiological features of Leigh syndrome and cytochrome oxidase deficiency was found to have a mutation in the COX15 gene. (PMID:15235026)
• cdkl3 transfected in anchorage-independent (suspension) HeLa cells overexpressed relative to attached cells and lead to elevated proliferation and viability relative to untransfected. Same in two HEK-293 and a CHO cell lines. (PMID:17945021)
• COX 15 mRNA was significantly more abundant in the cerebral tissue of Alzheimer’s disease (AD) patients and COX10 and COX15 SNP were significantly less represented in the patient group, suggesting a possible protective role toward the risk for AD (PMID:19826901)
• The expression of the AOX, well-tolerated by the cells, compensates for both the growth defect and the pronounced oxidant-sensitivity of COX-deficient human cells. (PMID:20049701)
• Mutations of COX15 causing single amino acid conversions are associated with fatal infantile hypertrophic cardiomyopathy and the neurological disorder Leigh syndrome. (PMID:26940873)
• Phenotypic variability and mutation hotspot in COX15-related Leigh syndrome. (PMID:32232962)
• Cox15 is a novel oncogene that required for lung cancer cell proliferation. (PMID:34547626)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cox15	ENSDARG00000075933
mus_musculus	Cox15	ENSMUSG00000040018
rattus_norvegicus	Cox15	ENSRNOG00000017230
drosophila_melanogaster	CG3803	FBGN0034938
caenorhabditis_elegans		WBGENE00011526

Protein

Protein identifiers

Heme A synthase COX15 — Q7KZN9 (reviewed: Q7KZN9)

Alternative names: Cytochrome c oxidase assembly protein COX15 homolog

All UniProt accessions (1): Q7KZN9

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the second reaction in the biosynthesis of heme A, a prosthetic group of mitochondrial cytochrome c oxidase (CcO). Heme A is synthesized from heme B by two sequential enzymatic reactions catalyzed by heme O synthase (HOS) and heme A synthase (HAS). HAS catalyzes the conversion of heme O to heme A by two successive hydroxylations of the methyl group at C8, in a reaction that involves matrix ferredoxin and ferredoxin reductase. The first hydroxylation forms heme I, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme A.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Predominantly found in tissues characterized by high rates of oxidative phosphorylation (OxPhos), including muscle, heart, and brain.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 6 (MC4DN6) [MIM:615119] An autosomal recessive multisystem disorder with variable manifestations. Some patients present in the neonatal period with encephalomyopathic features, whereas others present later in the first year of life with developmental regression. Clinical features include microcephaly, encephalopathy, hypertrophic cardiomyopathy, persistent lactic acidosis, respiratory distress, hypotonia and seizures. Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-half (TM1-TM4) and C-half (TM5-TM8) domains are connected by an intracellular loop. Each domain is formed from four-helix bundles and they align in a pseudo twofold symmetry manner. The N-half domain is the substrate heme O binding domain and the C-half domain is the cofactor heme B binding domain.

Pathway. Porphyrin-containing compound metabolism; heme A biosynthesis; heme A from heme O: step 1/1.

Similarity. Belongs to the COX15/CtaA family. Type 2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7KZN9-1	1, COX15.1	yes
Q7KZN9-2	2, COX15.2

RefSeq proteins (10): NP_001307903, NP_001307904, NP_001307905, NP_001358953, NP_001358954, NP_001358955, NP_001358956, NP_001358957, NP_004367, NP_510870* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003780	COX15/CtaA_fam	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR023754	HemeA_synthase_2	Family

Pfam: PF02628

Catalyzed reactions (Rhea), 1 shown:

• Fe(II)-heme o + 2 A + H2O = Fe(II)-heme a + 2 AH2 (RHEA:63388)

UniProt features (28 total): topological domain 9, transmembrane region 8, binding site 4, sequence conflict 3, sequence variant 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7KZN9-F1	85.29	0.70

Functional residue map

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

Ligand- & substrate-binding residues (4): 152 (axial binding residue); 226 (axial binding residue); 326 (axial binding residue); 387 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 205 (showing top): GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, REACTOME_METABOLISM_OF_PORPHYRINS, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, FONTAINE_PAPILLARY_THYROID_CARCINOMA_UP, VANHARANTA_UTERINE_FIBROID_WITH_7Q_DELETION_DN, GOBP_TETRAPYRROLE_METABOLIC_PROCESS, GOBP_PIGMENT_METABOLIC_PROCESS, GOCC_MITOCHONDRIAL_ENVELOPE, DOUGLAS_BMI1_TARGETS_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, NRF2_01, GOBP_PIGMENT_BIOSYNTHETIC_PROCESS, DANG_BOUND_BY_MYC

GO Biological Process (3): heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), cytochrome complex assembly (GO:0017004)

GO Molecular Function (7): oxidoreductase activity, acting on the CH-CH group of donors (GO:0016627), oxidoreductase activity, acting on NAD(P)H, heme protein as acceptor (GO:0016653), heme binding (GO:0020037), metal ion binding (GO:0046872), heme A synthase activity (GO:0120547), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (6): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), cytochrome complex (GO:0070069), respiratory chain complex (GO:0098803), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of porphyrins	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
heme biosynthetic process	1
protein-containing complex assembly	1
oxidoreductase activity	1
oxidoreductase activity, acting on NAD(P)H	1
tetrapyrrole binding	1
cation binding	1
oxidoreductase activity, acting on CH or CH2 groups	1
binding	1
catalytic activity	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
catalytic complex	1
protein-containing complex	1

Protein interactions and networks

STRING

1876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX15	SURF1	Q15526	961
COX15	COX10	Q12887	949
COX15	SCO2	O43819	925
COX15	SCO1	O75880	910
COX15	PET117	Q6UWS5	909
COX15	TACO1	Q9BSH4	884
COX15	COX6B1	P14854	854
COX15	MT-CO3	P00414	848
COX15	LRPPRC	P42704	800
COX15	MT-CO1	P00395	799
COX15	COA3	Q9Y2R0	797
COX15	BCS1L	Q9Y276	789
COX15	MT-CO2	P00403	783
COX15	COX5A	P20674	782
COX15	COX11	Q9Y6N1	773

IntAct

59 interactions, top by confidence:

A	B	Type	Score
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
ATP5F1B	SCAMP2	psi-mi:“MI:0914”(association)	0.530
COX15	SLC25A3	psi-mi:“MI:0914”(association)	0.530
COX15	PRDX6	psi-mi:“MI:0915”(physical association)	0.500
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ORF26	ATP1B1	psi-mi:“MI:0914”(association)	0.350
COX15	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
COX15	MYO1C	psi-mi:“MI:0914”(association)	0.350
COX15	SAP18	psi-mi:“MI:0914”(association)	0.350
	TSPO	psi-mi:“MI:0914”(association)	0.350
APP	MGST3	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
CLN3	ESYT2	psi-mi:“MI:0914”(association)	0.350
CRELD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
KCNK1	TMEM223	psi-mi:“MI:0914”(association)	0.350
ATP5PF	TMEM120B	psi-mi:“MI:0914”(association)	0.350
SLC1A1	UBXN8	psi-mi:“MI:0914”(association)	0.350
ATP2A3	UBXN8	psi-mi:“MI:0914”(association)	0.350
AQP3	UBXN8	psi-mi:“MI:0914”(association)	0.350
VIPR1	SLC33A1	psi-mi:“MI:0914”(association)	0.350
SLC2A1	SLC33A1	psi-mi:“MI:0914”(association)	0.350
ATP5F1C	EI24	psi-mi:“MI:0914”(association)	0.350

BioGRID (410): COX15 (Affinity Capture-MS), FLOT1 (Affinity Capture-MS), RPL12 (Affinity Capture-MS), FLOT2 (Affinity Capture-MS), CHMP4B (Affinity Capture-MS), RPL27 (Affinity Capture-MS), CENPV (Affinity Capture-MS), PABPC1 (Affinity Capture-MS), RPL30 (Affinity Capture-MS), ILF2 (Affinity Capture-MS), RPL10A (Affinity Capture-MS), SAP18 (Affinity Capture-MS), CHMP4A (Affinity Capture-MS), RPL28 (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS)

ESM2 similar proteins: A2AE42, A3A9H6, A3KPR5, A5D9A7, C4IYS8, O14569, O46522, P04839, P10897, P49447, P52649, Q08DG6, Q3T130, Q4V8K1, Q503V1, Q53TN4, Q5CZL8, Q5E965, Q5RAJ4, Q5RCZ2, Q5RKJ2, Q5RKL5, Q5U2W7, Q60720, Q641Y1, Q658P3, Q66IV3, Q687X5, Q6DDR3, Q6DHB5, Q6I681, Q6P1H1, Q7KZN9, Q7XMK3, Q86TG1, Q8BJ03, Q8CIZ9, Q8L856, Q8N8Q1, Q8NBI2

Diamond homologs: A1B8C2, A1USH8, A3PQK0, A4WZ55, A4YVQ0, A5CF77, A5EKD5, A5FA69, A5FXV4, A5VF68, A5VPX0, A6U7T3, A6X1W1, A7HXA1, A7ING5, A8EY08, A8F119, A8GMQ9, A8GRD0, A8GXM1, A8I7Y5, A8LK55, A9HEV3, A9IVC8, A9MAG4, A9W350, B0BWT1, B0CLB4, B0T0S6, B0UR12, B1M282, B1ZGD8, B2IH44, B2S532, B3CLF8, B3CRU7, B3PVH0, B3QKF4, B5ZXY9, B6IUZ7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 76 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	5	22.4×	3e-04
Mitochondrial protein degradation	9	20.1×	1e-07
Aerobic respiration and respiratory electron transport	5	8.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	19
Uncertain significance	238
Likely benign	207
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074263	NC_000010.10:g.(?101478103)(101478257_?)del	Pathogenic
2425091	NC_000010.10:g.(?101483693)(101487340_?)del	Pathogenic
2699835	NM_078470.6(COX15):c.4C>T (p.Gln2Ter)	Pathogenic
2702897	NM_078470.6(COX15):c.819del (p.Thr274fs)	Pathogenic
2749253	NM_078470.6(COX15):c.467dup (p.Arg157fs)	Pathogenic
2750450	NM_078470.6(COX15):c.298dup (p.Val100fs)	Pathogenic
2757837	NM_078470.6(COX15):c.264_265del (p.Val89fs)	Pathogenic
2771724	NM_078470.6(COX15):c.416dup (p.Thr140fs)	Pathogenic
2809650	NM_078470.6(COX15):c.562dup (p.Cys188fs)	Pathogenic
2813897	NM_078470.6(COX15):c.371dup (p.Tyr124Ter)	Pathogenic
2817347	NC_000010.11:g.99724124del	Pathogenic
2856524	NM_078470.6(COX15):c.663C>A (p.Tyr221Ter)	Pathogenic
2873866	NM_078470.6(COX15):c.610dup (p.Ser204fs)	Pathogenic
2880772	NM_078470.6(COX15):c.507C>G (p.Tyr169Ter)	Pathogenic
2984566	NM_078470.6(COX15):c.559dup (p.Leu187fs)	Pathogenic
2998078	NM_078470.6(COX15):c.372C>A (p.Tyr124Ter)	Pathogenic
429754	NM_078470.6(COX15):c.281_282del (p.Glu94fs)	Pathogenic
4797868	NM_078470.6(COX15):c.830C>G (p.Ser277Ter)	Pathogenic
6175	NM_078470.6(COX15):c.649C>T (p.Arg217Trp)	Pathogenic
631620	NM_078470.6(COX15):c.784C>T (p.Arg262Ter)	Pathogenic
1704545	NM_078470.6(COX15):c.79_90+3delinsGACT	Likely pathogenic
1805607	NM_078470.6(COX15):c.839T>C (p.Phe280Ser)	Likely pathogenic
2000035	NM_078470.6(COX15):c.750+1G>T	Likely pathogenic
2184963	NM_078470.6(COX15):c.90+1G>A	Likely pathogenic
2233034	NM_078470.6(COX15):c.750+1G>A	Likely pathogenic
2701344	NM_078470.6(COX15):c.207_272+655del	Likely pathogenic
2806453	NM_078470.6(COX15):c.987+1G>A	Likely pathogenic
2837000	NM_078470.6(COX15):c.987+1G>T	Likely pathogenic
2854588	NM_078470.6(COX15):c.90+1G>C	Likely pathogenic
2886194	NM_078470.6(COX15):c.583-2A>G	Likely pathogenic

SpliceAI

1057 predictions. Top by Δscore:

Variant	Effect	Δscore
10:99716458:TTCC:T	acceptor_gain	1.0000
10:99716459:TCC:T	acceptor_gain	1.0000
10:99716459:TCCC:T	acceptor_loss	1.0000
10:99716460:CC:C	acceptor_gain	1.0000
10:99716460:CCC:C	acceptor_gain	1.0000
10:99716461:CC:C	acceptor_gain	1.0000
10:99716462:C:CC	acceptor_gain	1.0000
10:99716462:CTGC:C	acceptor_loss	1.0000
10:99716463:T:A	acceptor_loss	1.0000
10:99721064:GGCAA:G	acceptor_gain	1.0000
10:99721066:CAA:C	acceptor_gain	1.0000
10:99721069:C:CC	acceptor_gain	1.0000
10:99721070:T:C	acceptor_loss	1.0000
10:99721075:A:C	acceptor_gain	1.0000
10:99724122:CC:C	acceptor_gain	1.0000
10:99724123:CC:C	acceptor_gain	1.0000
10:99724134:C:CT	acceptor_gain	1.0000
10:99724134:C:T	acceptor_gain	1.0000
10:99724135:A:T	acceptor_gain	1.0000
10:99727433:ATACT:A	donor_loss	1.0000
10:99727434:TACTT:T	donor_loss	1.0000
10:99727435:ACTT:A	donor_loss	1.0000
10:99727436:CTT:C	donor_loss	1.0000
10:99727437:TTA:T	donor_loss	1.0000
10:99727438:TACA:T	donor_loss	1.0000
10:99727439:A:AC	donor_gain	1.0000
10:99727440:C:CA	donor_loss	1.0000
10:99727440:C:CG	donor_gain	1.0000
10:99727440:CA:C	donor_gain	1.0000
10:99727440:CAT:C	donor_gain	1.0000

AlphaMissense

2607 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:99714661:G:C	H387D	0.999
10:99718353:C:G	R327P	0.999
10:99727124:G:C	F142L	0.999
10:99727124:G:T	F142L	0.999
10:99727126:A:G	F142L	0.999
10:99714709:C:G	G371R	0.998
10:99718357:G:C	H326D	0.998
10:99718500:C:T	G278E	0.998
10:99720987:C:A	G278W	0.998
10:99723995:G:C	S237R	0.998
10:99723995:G:T	S237R	0.998
10:99723997:T:G	S237R	0.998
10:99724030:G:C	H226D	0.998
10:99727092:C:G	R153P	0.998
10:99727096:G:C	H152D	0.998
10:99727446:A:C	F130L	0.998
10:99727446:A:T	F130L	0.998
10:99727448:A:G	F130L	0.998
10:99729553:C:A	R91M	0.998
10:99729553:C:G	R91T	0.998
10:99714666:G:T	A385D	0.997
10:99714669:G:T	A384D	0.997
10:99714708:C:T	G371D	0.997
10:99720987:C:G	G278R	0.997
10:99720987:C:T	G278R	0.997
10:99724038:A:G	L223P	0.997
10:99724103:C:A	M201I	0.997
10:99724103:C:G	M201I	0.997
10:99724103:C:T	M201I	0.997
10:99727103:C:A	E149D	0.997

dbSNP variants (sampled 300 via entrez): RS1000205963 (10:99733181 C>T), RS1000225970 (10:99698445 A>G), RS1000382040 (10:99705317 A>G), RS1000416338 (10:99698320 G>A,T), RS1000448621 (10:99698194 C>T), RS1000489489 (10:99732367 T>C,G), RS1000509325 (10:99697121 T>C), RS1000561817 (10:99696792 C>A), RS1000666162 (10:99704027 C>A), RS1000689786 (10:99707288 C>A), RS1000825478 (10:99710980 T>C), RS1000984 (10:99710328 C>A,T), RS1001033047 (10:99733512 C>G), RS1001049838 (10:99717730 C>A,G), RS1001120994 (10:99703693 A>C,G)

Disease associations

OMIM: gene MIM:603646 | disease phenotypes: MIM:256000, MIM:615119

GenCC curated gene-disease

Disease	Classification	Inheritance
cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2	Definitive	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
Leigh syndrome	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Limited	AR

Mondo (4): Leigh syndrome (MONDO:0009723), cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 (MONDO:0014051), cardiomyopathy (MONDO:0004994), (MONDO:0016815)

Orphanet (3): Fatal infantile cytochrome C oxidase deficiency (Orphanet:1561), Leigh syndrome (Orphanet:506), Rare cardiomyopathy (Orphanet:167848)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000124	Renal tubular dysfunction
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000488	Retinopathy
HP:0000508	Ptosis
HP:0000580	Pigmentary retinopathy
HP:0000597	Ophthalmoparesis
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001348	Brisk reflexes
HP:0001397	Hepatic steatosis
HP:0001410	Decreased liver function
HP:0001427	Mitochondrial inheritance
HP:0001508	Failure to thrive
HP:0001558	Decreased fetal movement
HP:0001638	Cardiomyopathy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001903	Anemia
HP:0001994	Renal Fanconi syndrome

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001438_10	Crohn’s disease	5.000000e-07
GCST001762_86	Obesity-related traits	6.000000e-06
GCST003017_4	Colorectal cancer	8.000000e-07
GCST003017_9	Colorectal cancer	4.000000e-08
GCST007856_1	Colorectal cancer or advanced adenoma	4.000000e-06
GCST007856_18	Colorectal cancer or advanced adenoma	7.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067143 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	3
Acetaminophen	increases expression, decreases expression	2
Copper Sulfate	decreases expression, increases expression	2
bisphenol A	decreases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
corosolic acid	decreases expression	1
K 7174	decreases expression	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Bilirubin	decreases expression	1
Doxorubicin	decreases expression	1
Environmental Pollutants	affects expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Sarin	decreases expression, increases expression	1
T-2 Toxin	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Thimerosal	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
CHEMBL5651169	Binding	Binding affinity to human COX15 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)

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

Trial	Phase	Status	Title
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome