COX6A1

Summary

COX6A1 (cytochrome c oxidase subunit 6A1, HGNC:2277) is a protein-coding gene on chromosome 12q24.31, encoding Cytochrome c oxidase subunit 6A1, mitochondrial (P12074). 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: 48.5% of cell lines).

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in the electron transfer and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes polypeptide 1 (liver isoform) of subunit VIa, and polypeptide 1 is found in all non-muscle tissues. Polypeptide 2 (heart/muscle isoform) of subunit VIa is encoded by a different gene, and is present only in striated muscles. These two polypeptides share 66% amino acid sequence identity. It has been reported that there may be several pseudogenes on chromosomes 1, 6, 7q21, 7q31-32 and 12. However, only one pseudogene (COX6A1P) on chromosome 1p31.1 has been documented.

Source: NCBI Gene 1337 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Strong, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 124 total — 1 pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 48.5% of screened cell lines
• MANE Select transcript: NM_004373

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2277
Approved symbol	COX6A1
Name	cytochrome c oxidase subunit 6A1
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	COX6AL
Ensembl gene	ENSG00000111775
Ensembl biotype	protein_coding
OMIM	602072
Entrez	1337

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 retained_intron

ENST00000229379, ENST00000549525, ENST00000550009, ENST00000932192

RefSeq mRNA: 1 — MANE Select: NM_004373 NM_004373

CCDS: CCDS9197

Canonical transcript exons

ENST00000229379 — 3 exons

Exon	Start	End
ENSE00001034501	120440454	120440730
ENSE00003461317	120438113	120438229
ENSE00003596274	120438379	120438521

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 99.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 232.8676 / max 2545.6143, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128342	185.2871	1828
128341	46.9816	1821
128340	0.5989	363

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	99.87	gold quality
primary visual cortex	UBERON:0002436	99.83	gold quality
frontal cortex	UBERON:0001870	99.82	gold quality
temporal lobe	UBERON:0001871	99.82	gold quality
amygdala	UBERON:0001876	99.82	gold quality
frontal lobe	UBERON:0016525	99.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.81	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.81	gold quality
cerebral cortex	UBERON:0000956	99.79	gold quality
substantia nigra	UBERON:0002038	99.79	gold quality
superior frontal gyrus	UBERON:0002661	99.79	gold quality
Ammon’s horn	UBERON:0001954	99.78	gold quality
right frontal lobe	UBERON:0002810	99.78	gold quality
anterior cingulate cortex	UBERON:0009835	99.78	gold quality
mucosa of transverse colon	UBERON:0004991	99.76	gold quality
hypothalamus	UBERON:0001898	99.75	gold quality
putamen	UBERON:0001874	99.74	gold quality
caudate nucleus	UBERON:0001873	99.73	gold quality
nucleus accumbens	UBERON:0001882	99.73	gold quality
brain	UBERON:0000955	99.69	gold quality
adult mammalian kidney	UBERON:0000082	99.60	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.58	gold quality
cortex of kidney	UBERON:0001225	99.55	gold quality
transverse colon	UBERON:0001157	99.54	gold quality
metanephros cortex	UBERON:0010533	99.54	gold quality
duodenum	UBERON:0002114	99.52	gold quality
pituitary gland	UBERON:0000007	99.47	gold quality
adenohypophysis	UBERON:0002196	99.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.47	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.47	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	49.23
E-MTAB-7316	yes	24.38
E-HCAD-10	yes	15.13
E-MTAB-10042	yes	9.61
E-HCAD-5	no	1811.86
E-GEOD-111727	no	1619.91
E-MTAB-8559	no	1059.59
E-MTAB-10596	no	964.69
E-HCAD-31	no	2.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, MEF2A, NFE2L2, NRF1, SP1, YY1

miRNA regulators (miRDB)

15 targeting COX6A1, 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-7152-3P	99.97	67.47	849
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-203B-5P	97.24	68.54	543
HSA-MIR-6718-5P	97.24	68.15	553
HSA-MIR-3663-5P	97.01	64.84	713

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 48.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• COX6A1 was identified as the protein that inhibits yeast cells Bax-sensitivity and protects mammalian cells from 4-HPR-induced apoptosis. (PMID:18549809)
• Data found that subunits Cox6a, Cox6b and Cox7a assembled into pre-existing complex IV, while Cox4-1 and Cox6c subunits assembled into subcomplexes that may represent rate-limiting intermediates. (PMID:19843159)
• Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 6a (PMID:20307258)
• Mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. (PMID:25152455)
• We demonstrate a developmental isoform switch of COX6A and COX7A subunits in human and mouse skeletal muscle (PMID:25666558)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cox6a2	ENSDARG00000054588
mus_musculus	Cox6a1	ENSMUSG00000041697
rattus_norvegicus	Cox6a1	ENSRNOG00000001170
drosophila_melanogaster	COX6AL2	FBGN0036830
drosophila_melanogaster	COX6AL	FBGN0050093
caenorhabditis_elegans		WBGENE00006519

Paralogs (1): COX6A2 (ENSG00000156885)

Protein

Protein identifiers

Cytochrome c oxidase subunit 6A1, mitochondrial — P12074 (reviewed: P12074)

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

All UniProt accessions (2): P12074, H6SG15

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.

Subunit / interactions. Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and COXFA4, which are encoded in the nuclear genome. The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)).

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Charcot-Marie-Tooth disease, recessive intermediate D (CMTRID) [MIM:616039] A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Energy metabolism; oxidative phosphorylation.

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

RefSeq proteins (1): NP_004364* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF02046

UniProt features (5 total): topological domain 2, transit peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9I6F	ELECTRON MICROSCOPY	2.95
9I7U	ELECTRON MICROSCOPY	3.15
5Z62	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12074-F1	84.06	0.60

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

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

MSigDB gene sets: 241 (showing top): GGGACCA_MIR133A_MIR133B, MODULE_93, KAAB_FAILED_HEART_ATRIUM_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, MORF_UBE2I, MORF_HDAC1, MORF_RAD21, HSIAO_HOUSEKEEPING_GENES, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, MORF_SKP1A, MARTINEZ_RB1_TARGETS_DN, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_ELECTRON_TRANSPORT_CHAIN, KEGG_HUNTINGTONS_DISEASE

GO Biological Process (4): generation of precursor metabolites and energy (GO:0006091), mitochondrial electron transport, cytochrome c to oxygen (GO:0006123), cellular respiration (GO:0045333), oxidative phosphorylation (GO:0006119)

GO Molecular Function (3): oxidoreductase activity (GO:0016491), enzyme regulator activity (GO:0030234), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial membrane (GO:0031966), respiratory chain complex IV (GO:0045277), sperm principal piece (GO:0097228), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	2
cellular anatomical structure	2
metabolic process	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
energy derivation by oxidation of organic compounds	1
aerobic respiration	1
proton motive force-driven ATP synthesis	1
molecular function regulator activity	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1
sperm flagellum	1

Protein interactions and networks

STRING

1767 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX6A1	COX6B1	P14854	985
COX6A1	COX5B	P10606	966
COX6A1	COX5A	P20674	959
COX6A1	COX7A2	P14406	927
COX6A1	COXFA4	O00483	915
COX6A1	COX6C	P09669	904
COX6A1	COX7A1	P24310	870
COX6A1	COX4I1	P13073	853
COX6A1	COX7C	P15954	846
COX6A1	COX8A	P10176	838
COX6A1	COX7B	P24311	837
COX6A1	COX4I2	Q96KJ9	798
COX6A1	GABPA	Q06546	773
COX6A1	COX7A2L	O14548	727
COX6A1	CYCS	P00001	645

IntAct

58 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
COX6A1	HTT	psi-mi:“MI:0915”(physical association)	0.670
COX6A1	LXN	psi-mi:“MI:0915”(physical association)	0.560
COQ2	SLC25A5	psi-mi:“MI:0914”(association)	0.530
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
NMES1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
CHCHD10	TIMM44	psi-mi:“MI:0914”(association)	0.350
CHCHD2	POLRMT	psi-mi:“MI:0914”(association)	0.350
CISD3	POLRMT	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
COX6B1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NUDT19	psi-mi:“MI:0914”(association)	0.350
NDUFS3	ACOT7	psi-mi:“MI:0914”(association)	0.350
NME4	NRDC	psi-mi:“MI:0914”(association)	0.350
OCIAD1	NDUFS8	psi-mi:“MI:0914”(association)	0.350
CHCHD10	RNASEH1	psi-mi:“MI:0914”(association)	0.350
COX6B1	NDUFS4	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NMES1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
CHCHD10	ACSL4	psi-mi:“MI:0914”(association)	0.350
CHCHD2	ACSL4	psi-mi:“MI:0914”(association)	0.350

BioGRID (62): COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-MS), COX6A1 (Affinity Capture-RNA), COX6A1 (Affinity Capture-MS), COX7C (Co-fractionation)

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

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

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
COX6A1	“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 56 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
Respiratory electron transport	6	13.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	58
Likely benign	52
Benign	6

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
156370	NM_004373.4(COX6A1):c.247-7_247-3del	Pathogenic

SpliceAI

399 predictions. Top by Δscore:

Variant	Effect	Δscore
12:120438377:A:AG	acceptor_gain	1.0000
12:120438378:G:GG	acceptor_gain	1.0000
12:120438519:AAGGT:A	donor_loss	1.0000
12:120438520:AGGTA:A	donor_loss	1.0000
12:120438521:GGT:G	donor_loss	1.0000
12:120438522:G:GG	donor_gain	1.0000
12:120438523:T:G	donor_loss	1.0000
12:120440453:GCC:G	acceptor_gain	1.0000
12:120440617:G:GG	donor_gain	1.0000
12:120440625:GACCT:G	donor_gain	1.0000
12:120438373:CCGCA:C	acceptor_loss	0.9900
12:120438374:CGCA:C	acceptor_loss	0.9900
12:120438375:GCA:G	acceptor_loss	0.9900
12:120438376:CAGCT:C	acceptor_loss	0.9900
12:120438377:A:C	acceptor_loss	0.9900
12:120438378:G:GT	acceptor_loss	0.9900
12:120438378:GCTC:G	acceptor_gain	0.9900
12:120438520:AG:A	donor_gain	0.9900
12:120438521:GG:G	donor_gain	0.9900
12:120440421:T:TA	acceptor_gain	0.9900
12:120440452:A:AG	acceptor_gain	0.9900
12:120440453:G:GG	acceptor_gain	0.9900
12:120440453:GCCGT:G	acceptor_gain	0.9900
12:120440629:T:G	donor_gain	0.9900
12:120440629:T:TG	donor_gain	0.9900
12:120438225:CTCAG:C	donor_loss	0.9800
12:120438226:TCAGG:T	donor_loss	0.9800
12:120438227:CAGGT:C	donor_loss	0.9800
12:120438228:AG:A	donor_loss	0.9800
12:120438229:GGT:G	donor_loss	0.9800

AlphaMissense

699 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:120438409:T:A	V45D	0.997
12:120438412:C:A	A46E	0.997
12:120438432:A:C	S53R	0.997
12:120438434:C:A	S53R	0.997
12:120438434:C:G	S53R	0.997
12:120438486:T:C	F71L	0.997
12:120438488:C:A	F71L	0.997
12:120438488:C:G	F71L	0.997
12:120440463:T:A	W86R	0.997
12:120440463:T:C	W86R	0.997
12:120438387:T:A	W38R	0.996
12:120438387:T:C	W38R	0.996
12:120438430:T:A	V52D	0.996
12:120440465:G:C	W86C	0.996
12:120440465:G:T	W86C	0.996
12:120440473:G:T	G89V	0.996
12:120438420:G:A	G49R	0.995
12:120438420:G:C	G49R	0.995
12:120438421:G:A	G49E	0.995
12:120438515:G:C	R80S	0.995
12:120438515:G:T	R80S	0.995
12:120440457:T:C	F84L	0.995
12:120440459:T:A	F84L	0.995
12:120440459:T:G	F84L	0.995
12:120438389:G:C	W38C	0.994
12:120438389:G:T	W38C	0.994
12:120438418:C:A	P48H	0.994
12:120438427:C:A	A51E	0.994
12:120438514:G:C	R80T	0.994
12:120440490:C:G	H95D	0.994

dbSNP variants (sampled 300 via entrez): RS1000338369 (12:120438640 A>C), RS1000840044 (12:120439576 G>A), RS1000950205 (12:120439806 G>T), RS1001062748 (12:120440731 G>T), RS1001402707 (12:120440070 T>G), RS1001847232 (12:120441038 T>A), RS1002314517 (12:120439411 C>T), RS1002627792 (12:120439267 C>A), RS1002985929 (12:120436698 G>A), RS1003107890 (12:120436737 C>CA), RS1003968164 (12:120441002 C>G), RS1005459002 (12:120438823 G>A,T), RS1005903023 (12:120438604 A>C,G), RS1006129331 (12:120437831 C>T), RS1006517634 (12:120439660 C>G)

Disease associations

OMIM: gene MIM:602072 | disease phenotypes: MIM:616039, MIM:201470

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease recessive intermediate D	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Strong	AR

Mondo (3): Charcot-Marie-Tooth disease recessive intermediate D (MONDO:0014467), short chain acyl-CoA dehydrogenase deficiency (MONDO:0008722), peripheral neuropathy (MONDO:0005244)

Orphanet (2): Autosomal recessive intermediate Charcot-Marie-Tooth disease type D (Orphanet:435998), Short chain acyl-CoA dehydrogenase deficiency (Orphanet:26792)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001761	Pes cavus
HP:0002936	Distal sensory impairment
HP:0003376	Steppage gait
HP:0003383	Onion bulb formation
HP:0003677	Slowly progressive
HP:0009027	Foot dorsiflexor weakness
HP:0009830	Peripheral neuropathy
HP:0011463	Childhood onset

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004401_6	Reading disability or specific language impairment (pleiotropy)	4.000000e-06
GCST004402_1	Reading disability or specific language impairment adjusted for intelligence quotient (pleiotropy)	1.000000e-06
GCST008103_87	Bipolar disorder	1.000000e-06
GCST90013407_144	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-22
GCST90020028_953	Hip circumference adjusted for BMI	5.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537596	Short chain Acyl CoA dehydrogenase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066963 (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
8.05	Kd	8.895	nM	CHEMBL5653589
8.05	ED50	8.895	nM	CHEMBL5653589

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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148131: Binding affinity to human COX6A1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0089	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	2
aristolochic acid I	increases expression	1
ginger extract	decreases expression, increases abundance	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
sodium arsenite	increases abundance, increases expression	1
chloropicrin	increases expression	1
OSW 1	increases expression	1
10’(Z),13’(E),15’(E)-heptadecatrienylhydroquinone	increases expression	1
5-hydroxythalidomide	affects binding	1
MT19c compound	decreases expression	1
bisphenol AF	increases expression	1
Arsenic	increases abundance, increases expression	1
Cadmium	increases expression, increases abundance	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Lipopolysaccharides	affects response to substance, affects expression	1
Methotrexate	decreases expression	1
Oils, Volatile	increases abundance, decreases expression	1
Rotenone	decreases expression	1
Sarin	decreases expression	1
Selenium	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	decreases expression	1
Isotretinoin	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Lactic Acid	increases expression	1
Particulate Matter	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
CHEMBL5651173	Binding	Binding affinity to human COX6A1 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

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1UF	HAP1 COX6A1 (-) 2	Cancer cell line	Male
CVCL_E1UG	HAP1 COX6A1 (-) 3	Cancer cell line	Male
CVCL_E1UH	HAP1 COX6A1 (-) 4	Cancer cell line	Male
CVCL_E1UI	HAP1 COX6A1 (-) 5	Cancer cell line	Male
CVCL_E1UJ	HAP1 COX6A1 (-) 6	Cancer cell line	Male
CVCL_XM94	HAP1 COX6A1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06759272	PHASE4	NOT_YET_RECRUITING	Impact of CYP2C19 Genotype-guided Approach in Antiplatelet Therapy on Platelet Reactivity Index Among Coronary Artery Disease (CAD) Patients
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy