COXFA4

Summary

COXFA4 (cytochrome c oxidase associated subunit FA4, HGNC:7687) is a protein-coding gene on chromosome 7p21.3, encoding Cytochrome c oxidase subunit FA4 (O00483). 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: 39.7% of cell lines).

The protein encoded by this gene belongs to the complex I 9kDa subunit family. Mammalian complex I of mitochondrial respiratory chain is composed of 45 different subunits. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.

Source: NCBI Gene 4697 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 80 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 39.7% of screened cell lines
• MANE Select transcript: NM_002489

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7687
Approved symbol	COXFA4
Name	cytochrome c oxidase associated subunit FA4
Location	7p21.3
Locus type	gene with protein product
Status	Approved
Aliases	MLRQ, CI-9k, MRCAF1, MISTR1
Ensembl gene	ENSG00000189043
Ensembl biotype	protein_coding
OMIM	603833
Entrez	4697

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000339600, ENST00000463308, ENST00000470761, ENST00000482299, ENST00000486007, ENST00000492822, ENST00000855674, ENST00000923092, ENST00000923093

RefSeq mRNA: 1 — MANE Select: NM_002489 NM_002489

CCDS: CCDS5357

Canonical transcript exons

ENST00000339600 — 4 exons

Exon	Start	End
ENSE00001375746	10940016	10940153
ENSE00001381181	10931943	10933692
ENSE00003459616	10938090	10938147
ENSE00003676225	10938808	10938896

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 312.8000 / max 3197.9375, expressed in 1826 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82749	303.6418	1826
82748	9.1582	1677

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.93	gold quality
myocardium	UBERON:0002349	99.85	gold quality
cerebellar vermis	UBERON:0004720	99.80	gold quality
left ventricle myocardium	UBERON:0006566	99.80	gold quality
pons	UBERON:0000988	99.78	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.78	gold quality
prefrontal cortex	UBERON:0000451	99.76	gold quality
biceps brachii	UBERON:0001507	99.76	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.73	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.73	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.70	gold quality
vastus lateralis	UBERON:0001379	99.67	gold quality
diaphragm	UBERON:0001103	99.66	gold quality
orbitofrontal cortex	UBERON:0004167	99.66	gold quality
adult organism	UBERON:0007023	99.66	gold quality
quadriceps femoris	UBERON:0001377	99.65	gold quality
vena cava	UBERON:0004087	99.65	gold quality
parietal lobe	UBERON:0001872	99.64	gold quality
postcentral gyrus	UBERON:0002581	99.64	gold quality
cardiac atrium	UBERON:0002081	99.62	gold quality
superior vestibular nucleus	UBERON:0007227	99.62	gold quality
cardiac ventricle	UBERON:0002082	99.61	gold quality
heart left ventricle	UBERON:0002084	99.61	gold quality
renal medulla	UBERON:0000362	99.60	gold quality
frontal cortex	UBERON:0001870	99.60	gold quality
substantia nigra pars compacta	UBERON:0001965	99.60	gold quality
lateral globus pallidus	UBERON:0002476	99.60	gold quality
right atrium auricular region	UBERON:0006631	99.60	gold quality
triceps brachii	UBERON:0001509	99.59	gold quality
superior frontal gyrus	UBERON:0002661	99.58	gold quality

Single-cell (SCXA)

Detected in 25 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	5076.03
E-GEOD-84465	yes	1638.34
E-GEOD-81547	yes	488.82
E-HCAD-1	yes	74.18
E-HCAD-4	yes	51.08
E-MTAB-5061	yes	28.34
E-MTAB-8410	yes	25.58
E-HCAD-10	yes	13.27
E-HCAD-11	yes	12.64
E-GEOD-83139	yes	12.37
E-CURD-112	yes	12.36
E-MTAB-10042	yes	11.79
E-MTAB-8142	yes	11.49
E-CURD-46	yes	10.89
E-GEOD-135922	yes	10.65

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

114 targeting COXFA4, 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-4668-3P	100.00	68.74	2635
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6783-3P	99.89	67.92	2059

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 39.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• Findings support reassignment of the NDUFA4 protein to complex IV and suggest that patients with unexplained COX deficiency should be screened for NDUFA4 mutations. (PMID:23746447)
• Results found that NDUFA4 mRNAs are upregulated and associated with oxidative phosphorylation pathway in gastric cancer. Also, NDUFA4 seems to promote the proliferation, reduce apoptosis, and regulate the oxidative phosphorylation pathway in gastric cancer cells. (PMID:30238562)
• NDUFA4 was identified as a direct target of miR-147b and knockdown of NDUFA4 abolished the oncogenic role of miR-147b inhibitor. (PMID:30348529)
• Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity. (PMID:33837217)
• m6A RNA methylation-mediated NDUFA4 promotes cell proliferation and metabolism in gastric cancer. (PMID:35977935)
• A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants. (PMID:36206731)
• NDUFA4 promotes cell proliferation by enhancing oxidative phosphorylation in pancreatic adenocarcinoma. (PMID:36307669)
• NDUFA4 promotes the progression of head and neck paraganglioma by inhibiting ferroptosis. (PMID:37602474)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufa4b	ENSDARG00000056108
danio_rerio	ndufa4a	ENSDARG00000099499
mus_musculus	Ndufa4	ENSMUSG00000029632
rattus_norvegicus	Ndufa4	ENSRNOG00000005512

Paralogs (2): C15orf48 (ENSG00000166920), NDUFA4L2 (ENSG00000185633)

Protein

Protein identifiers

Cytochrome c oxidase subunit FA4 — O00483 (reviewed: O00483)

Alternative names: Complex I-MLRQ, Cytochrome c oxidase subunit NDUFA4, NADH-ubiquinone oxidoreductase MLRQ subunit

All UniProt accessions (1): O00483

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. COXFA4 is required for complex IV maintenance.

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 RAB5IF. Interacts with FLVCR2; this interaction occurs in the absence of heme and is disrupted upon heme binding.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 21 (MC4DN21) [MIM:619065] An autosomal recessive mitochondrial disorder with onset in infancy. MC4DN21 is characterized by congenital lactic acidosis, encephalopathy, global developmental delay, delayed speech, motor dysfunction, dystonia, and spasticity. Ataxia, peripheral neuropathy, and seizures may also occur. 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.

Miscellaneous. During complex IV purifications dissociates from complex IV upon treatment with standard detergent DDM (decyl beta-D-maltoside) in high concentrations.

Similarity. Belongs to the complex IV COXFA4 subunit family.

RefSeq proteins (1): NP_002480* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010530	B12D	Family

Pfam: PF06522

UniProt features (6 total): topological domain 2, modified residue 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00483-F1	91.85	0.75

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 (2): 10, 66

Function

Pathways and Gene Ontology

Reactome pathways

13 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
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711123	Cellular response to chemical stress

MSigDB gene sets: 308 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, MODULE_93, MODULE_151, MODULE_77, GCANCTGNY_MYOD_Q6, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, HSIAO_HOUSEKEEPING_GENES, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, NKX61_01, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_ELECTRON_TRANSPORT_CHAIN, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, KEGG_HUNTINGTONS_DISEASE

GO Biological Process (4): mitochondrial electron transport, NADH to ubiquinone (GO:0006120), mitochondrial electron transport, cytochrome c to oxygen (GO:0006123), cellular respiration (GO:0045333), proton transmembrane transport (GO:1902600)

GO Molecular Function (3): NADH dehydrogenase (ubiquinone) activity (GO:0008137), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial membrane (GO:0031966), respiratory chain complex I (GO:0045271), respiratory chain complex IV (GO:0045277), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-10 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
Metabolism	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Generic Transcription Pathway	1
Gene expression (Transcription)	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aerobic electron transport chain	2
mitochondrial ATP synthesis coupled electron transport	2
binding	2
respiratory chain complex	2
transmembrane transporter complex	2
energy derivation by oxidation of organic compounds	1
monoatomic cation transmembrane transport	1
NADH dehydrogenase activity	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor	1
active monoatomic ion transmembrane transporter activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
NADH dehydrogenase complex	1
cytochrome complex	1
oxidoreductase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1730 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COXFA4	COXFA4L3	Q9C002	965
COXFA4	NDUFA2	O43678	963
COXFA4	COX6A1	P12074	915
COXFA4	COX6B1	P14854	911
COXFA4	COX6A2	Q02221	853
COXFA4	NDUFA5	Q16718	822
COXFA4	NDUFA1	O15239	808
COXFA4	COX7C	P15954	798
COXFA4	COX6C	P09669	775
COXFA4	NDUFB8	O95169	765
COXFA4	COX7B	P24311	765
COXFA4	COX7A1	P24310	763
COXFA4	COX7A2	P14406	755
COXFA4	NDUFB9	Q9Y6M9	754
COXFA4	NDUFB6	O95139	752

IntAct

140 interactions, top by confidence:

A	B	Type	Score
DDX19B	MIF4GD	psi-mi:“MI:0914”(association)	0.870
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DPF1	NDUFA4	psi-mi:“MI:0915”(physical association)	0.560
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
UST	GOLIM4	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
PARP2	NDUFA4	psi-mi:“MI:0557”(adp ribosylation reaction)	0.440
FLT4	ILVBL	psi-mi:“MI:0914”(association)	0.420
AATK	NDUFA4	psi-mi:“MI:0914”(association)	0.420
MET	NDUFA4	psi-mi:“MI:0914”(association)	0.420
MET	NDUFA4	psi-mi:“MI:2364”(proximity)	0.420
NDUFA2	NDUFS8	psi-mi:“MI:0915”(physical association)	0.400
	FER1L5	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
NDUFA12	NDUFS8	psi-mi:“MI:0914”(association)	0.350
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
Tubg1	BDP1	psi-mi:“MI:0914”(association)	0.350
Kat8	HCFC1	psi-mi:“MI:0914”(association)	0.350
NDUFA6	NDUFS8	psi-mi:“MI:0914”(association)	0.350
TK	AP3B1	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (409): NDUFA4 (Affinity Capture-MS), NDUFA4 (Affinity Capture-MS), NDUFA4 (Affinity Capture-MS), NDUFA4 (Affinity Capture-MS), NDUFA4 (Affinity Capture-MS), NDUFA4 (Affinity Capture-MS), NDUFA4 (Affinity Capture-MS), NDUFA4 (Affinity Capture-MS), NDUFA4 (Affinity Capture-MS), COX7C (Affinity Capture-MS), TBRG4 (Affinity Capture-MS), SLC25A6 (Affinity Capture-MS), SLC25A10 (Affinity Capture-MS), PI4KA (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS)

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: O00483, Q01321, Q0MQ97, Q0MQ98, Q0MQ99, Q3SZ44, Q3YAJ5, Q4FZG9, Q4R542, Q5RK28, Q62425, Q6PBH5, Q810Q5, Q9NRX3, Q9C002

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFA4	“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 133 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
Dengue Virus Attachment and Entry	5	14.6×	2e-03
Constitutive Signaling by Aberrant PI3K in Cancer	8	11.4×	1e-04
Complex I biogenesis	6	11.2×	1e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	9	9.8×	1e-04
RAF/MAP kinase cascade	11	7.5×	1e-04
PIP3 activates AKT signaling	10	7.5×	1e-04
Respiratory electron transport	7	7.5×	2e-03
Cytokine Signaling in Immune system	9	4.1×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	9	34.5×	1e-09
positive regulation of MAP kinase activity	5	29.5×	8e-05
cell surface receptor protein tyrosine kinase signaling pathway	15	23.7×	7e-14
substrate adhesion-dependent cell spreading	6	18.8×	8e-05
protein autophosphorylation	11	14.5×	7e-08
proton motive force-driven mitochondrial ATP synthesis	5	12.0×	4e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	16	11.4×	4e-10
aerobic respiration	5	11.3×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	21
Likely benign	35
Benign	11

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2444066	NM_002489.4(COXFA4):c.42+1del	Pathogenic
3898851	NM_002489.4(NDUFA4):c.43-1G>A	Pathogenic
977513	NM_002489.4(COXFA4):c.42+1G>C	Pathogenic
1176532	NM_002489.4(COXFA4):c.25del (p.Ala9fs)	Likely pathogenic
3255019	NM_002489.4(COXFA4):c.131+1G>A	Likely pathogenic

SpliceAI

667 predictions. Top by Δscore:

Variant	Effect	Δscore
7:10933693:C:CC	acceptor_gain	1.0000
7:10933694:T:C	acceptor_gain	1.0000
7:10933694:T:TC	acceptor_gain	1.0000
7:10938143:CCCAA:C	acceptor_gain	1.0000
7:10938144:CCAA:C	acceptor_gain	1.0000
7:10938144:CCAAC:C	acceptor_gain	1.0000
7:10938145:CAA:C	acceptor_gain	1.0000
7:10938145:CAAC:C	acceptor_gain	1.0000
7:10938148:C:CC	acceptor_gain	1.0000
7:10938872:C:CT	acceptor_gain	1.0000
7:10938873:A:T	acceptor_gain	1.0000
7:10938893:TCAA:T	acceptor_gain	1.0000
7:10938894:CAA:C	acceptor_gain	1.0000
7:10938894:CAAC:C	acceptor_gain	1.0000
7:10938897:C:CC	acceptor_gain	1.0000
7:10940015:CG:C	donor_gain	1.0000
7:10933700:C:CT	acceptor_gain	0.9900
7:10938084:GTTTA:G	donor_loss	0.9900
7:10938085:TTTAC:T	donor_loss	0.9900
7:10938086:TTACC:T	donor_loss	0.9900
7:10938087:TA:T	donor_loss	0.9900
7:10938089:C:G	donor_loss	0.9900
7:10938146:AA:A	acceptor_gain	0.9900
7:10938148:CT:C	acceptor_loss	0.9900
7:10938149:T:C	acceptor_loss	0.9900
7:10938802:ACTT:A	donor_loss	0.9900
7:10938803:CTT:C	donor_loss	0.9900
7:10938804:TTA:T	donor_loss	0.9900
7:10938805:TAC:T	donor_loss	0.9900
7:10938806:A:AC	donor_gain	0.9900

AlphaMissense

528 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:10933639:G:C	F81L	0.995
7:10933639:G:T	F81L	0.995
7:10933641:A:G	F81L	0.995
7:10938120:C:A	W53C	0.995
7:10938120:C:G	W53C	0.995
7:10938122:A:G	W53R	0.995
7:10938122:A:T	W53R	0.995
7:10938146:A:G	W45R	0.994
7:10938146:A:T	W45R	0.994
7:10938090:C:A	K63N	0.993
7:10938090:C:G	K63N	0.993
7:10938872:C:G	G23R	0.992
7:10938872:C:T	G23R	0.992
7:10938144:C:A	W45C	0.991
7:10938144:C:G	W45C	0.991
7:10938853:G:T	A29E	0.991
7:10938856:C:T	G28E	0.990
7:10938829:G:T	A37E	0.989
7:10938857:C:G	G28R	0.989
7:10938857:C:T	G28R	0.989
7:10938871:C:T	G23E	0.989
7:10938865:C:T	G25E	0.988
7:10938880:A:T	V20E	0.988
7:10938863:C:G	A26P	0.987
7:10938145:C:G	W45S	0.986
7:10938866:C:G	G25R	0.985
7:10938866:C:T	G25R	0.985
7:10938854:C:G	A29P	0.984
7:10938121:C:A	W53L	0.981
7:10933691:A:G	F64S	0.980

dbSNP variants (sampled 300 via entrez): RS1000523474 (7:10934471 C>T), RS1000697316 (7:10938734 T>C), RS1001000354 (7:10934263 C>T), RS1001309457 (7:10935220 T>C), RS1001420906 (7:10935032 G>A,C), RS1001859950 (7:10938503 T>A), RS1002331809 (7:10938240 T>A,C), RS1002928614 (7:10937367 C>A), RS1003265505 (7:10937524 C>T), RS1003426396 (7:10932919 A>G), RS1004167764 (7:10939051 G>A,T), RS1004708942 (7:10934709 C>T), RS1005163443 (7:10934984 T>C,G), RS1005170503 (7:10937996 T>A), RS1005183194 (7:10938170 A>C)

Disease associations

OMIM: gene MIM:603833 | disease phenotypes: MIM:619065

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex IV deficiency, nuclear type 1	Strong	Autosomal recessive
mitochondrial complex IV deficiency, nuclear type 21	Strong	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR
mitochondrial disease	Definitive	AR

Mondo (3): mitochondrial complex IV deficiency, nuclear type 21 (MONDO:0033656), mitochondrial complex IV deficiency, nuclear type 1 (MONDO:0700250), (MONDO:0016815)

Orphanet (0):

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000750	Delayed speech and language development
HP:0001251	Ataxia
HP:0001264	Spastic diplegia
HP:0001270	Motor delay
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001348	Brisk reflexes
HP:0001531	Failure to thrive in infancy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002490	Increased CSF lactate
HP:0003128	Lactic acidosis
HP:0003487	Babinski sign
HP:0003557	Increased variability in muscle fiber diameter
HP:0003577	Congenital onset
HP:0003688	Cytochrome C oxidase-negative muscle fibers
HP:0004322	Short stature
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0012240	Increased intramyocellular lipid droplets
HP:0500233	Increased CSF alanine concentration

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002579_19	Heschl’s gyrus morphology	6.000000e-06
GCST002927_7	Mercury levels	7.000000e-06
GCST004748_127	Lung cancer	2.000000e-06
GCST008476_33	Emphysema annual change measurement in smokers (percent low attenuation area)	8.000000e-06
GCST009267_9	Dental caries (decayed, missing and filled teeth)	3.000000e-06
GCST009391_1774	Metabolite levels	3.000000e-07
GCST010511_2	Response to radiotherapy in nasopharyngeal carcinoma (acute oral mucositis)	3.000000e-06
GCST011176_3	Stroke	2.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement
EFO:0010457	Alpha ketoglutarate measurement
EFO:0010480	fumarate measurement
EFO:0010509	maleate measurement
EFO:1001904	oral mucositis

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2317 (SINGLE PROTEIN), CHEMBL2363065 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

12 potent at pChembl≥5 of 26 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.75	IC50	18	nM	CHEMBL197472
7.26	IC50	55	nM	CHEMBL370213
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.63	IC50	2350	nM	R-(+)-MARMIN-6’-LINOLEATE
5.51	IC50	3080	nM	R-(+)-MARMIN-6’-OCTANOATE
5.43	IC50	3670	nM	R-(+)-MARMIN-6’-UNDECANOATE
5.43	IC50	3710	nM	R-(+)-MARMIN-6’-OCTANOATE
5.31	IC50	4900	nM	(+)-9’-ISOVALEROXYLARICIRESINOL
5.04	IC50	9100	nM	(+)-9’-ISOVALEROXYLARICIRESINOL

PubChem BioAssay actives

12 with measured affinity, of 36 total; 6 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
2,2-dimethyl-6-[3-(3,4,5-trimethoxyphenyl)prop-1-en-2-yl]-3,4-dihydrochromene	254861: Inhibitory concentration against NADH ubiquinone oxidoreductase	ic50	0.0180	uM
(3,4,5-trimethoxyphenyl)methyl 2,2-dimethylchromene-6-carboxylate	254861: Inhibitory concentration against NADH ubiquinone oxidoreductase	ic50	0.0550	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] undecanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.8700	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] (9Z,12Z)-octadeca-9,12-dienoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.9200	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] octanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	3.0800	uM
[(2S,3R,4R)-2-(4-hydroxy-3-methoxyphenyl)-4-[(4-hydroxy-3-methoxyphenyl)methyl]oxolan-3-yl]methyl 3-methylbutanoate	739269: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1,10-phenanthroline-induced HIF1 activation incubated for 30 mins prior to 1,10-phenanthroline-challenge measured after 16 hrs by luciferase reporter assay	ic50	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
Air Pollutants	affects expression, increases abundance, decreases expression	3
bisphenol A	increases expression, decreases expression	2
Arsenic	decreases expression, increases abundance, affects cotreatment, increases expression	2
Doxorubicin	affects expression, decreases expression	2
Rotenone	increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects response to substance, affects expression	1
arsenite	affects binding, increases reaction	1
arsenic trichloride	affects cotreatment, decreases expression, increases abundance	1
azoxystrobin	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
corosolic acid	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
bisphenol B	increases expression	1
bisphenol S	increases expression	1
LDN 193189	decreases expression, affects cotreatment	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	affects cotreatment, decreases expression	1
alpha-Chlorohydrin	affects expression, increases expression	1
Atrazine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Cisplatin	increases expression	1
Copper	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651882	Binding	Binding affinity to human NDUFA4 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

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3C1	Abcam HEK293T NDUFA4 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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