ATP5PO

Summary

ATP5PO (ATP synthase peripheral stalk subunit OSCP, HGNC:850) is a protein-coding gene on chromosome 21q22.11, encoding ATP synthase peripheral stalk subunit OSCP, mitochondrial (P48047). Subunit OSCP, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. It is a selective cancer dependency (DepMap: 28.2% of cell lines).

The protein encoded by this gene is a component of the F-type ATPase found in the mitochondrial matrix. F-type ATPases are composed of a catalytic core and a membrane proton channel. The encoded protein appears to be part of the connector linking these two components and may be involved in transmission of conformational changes or proton conductance.

Source: NCBI Gene 539 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Strong, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 66 total — 8 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 28.2% of screened cell lines
• MANE Select transcript: NM_001697

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:850
Approved symbol	ATP5PO
Name	ATP synthase peripheral stalk subunit OSCP
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Aliases	OSCP, ATPO
Ensembl gene	ENSG00000241837
Ensembl biotype	protein_coding
OMIM	600828
Entrez	539

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000290299, ENST00000417181, ENST00000418933, ENST00000429064, ENST00000431254, ENST00000484627, ENST00000487374, ENST00000491703, ENST00000495005, ENST00000496044, ENST00000652380, ENST00000892986, ENST00000892987, ENST00000892988, ENST00000892989, ENST00000892990, ENST00000892991, ENST00000918650, ENST00000918651, ENST00000918652, ENST00000918653, ENST00000918654, ENST00000918655, ENST00000918656, ENST00000918657, ENST00000918658

RefSeq mRNA: 1 — MANE Select: NM_001697 NM_001697

CCDS: CCDS13634

Canonical transcript exons

ENST00000290299 — 7 exons

Exon	Start	End
ENSE00003477232	33903935	33904021
ENSE00003503253	33903453	33903639
ENSE00003553754	33914450	33914500
ENSE00003608641	33907341	33907453
ENSE00003658594	33909082	33909211
ENSE00003664335	33912289	33912399
ENSE00003843595	33915728	33915804

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 99.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 167.9254 / max 1890.1340, expressed in 1826 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190267	164.2351	1826
190268	3.6903	1586

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart left ventricle	UBERON:0002084	99.71	gold quality
apex of heart	UBERON:0002098	99.65	gold quality
right atrium auricular region	UBERON:0006631	99.59	gold quality
heart	UBERON:0000948	99.57	gold quality
ganglionic eminence	UBERON:0004023	99.50	gold quality
embryo	UBERON:0000922	99.49	gold quality
gastrocnemius	UBERON:0001388	99.43	gold quality
mucosa of transverse colon	UBERON:0004991	99.43	gold quality
muscle of leg	UBERON:0001383	99.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.40	gold quality
rectum	UBERON:0001052	99.39	gold quality
muscle organ	UBERON:0001630	99.38	gold quality
skeletal muscle organ	UBERON:0014892	99.38	gold quality
cortical plate	UBERON:0005343	99.36	gold quality
body of stomach	UBERON:0001161	99.33	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.33	gold quality
metanephros cortex	UBERON:0010533	99.33	gold quality
nucleus accumbens	UBERON:0001882	99.32	gold quality
right frontal lobe	UBERON:0002810	99.31	gold quality
amygdala	UBERON:0001876	99.29	gold quality
substantia nigra	UBERON:0002038	99.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.29	gold quality
adult mammalian kidney	UBERON:0000082	99.28	gold quality
transverse colon	UBERON:0001157	99.28	gold quality
putamen	UBERON:0001874	99.28	gold quality
duodenum	UBERON:0002114	99.28	gold quality
fundus of stomach	UBERON:0001160	99.27	gold quality
hypothalamus	UBERON:0001898	99.27	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.27	gold quality
cerebral cortex	UBERON:0000956	99.26	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	9.31
E-MTAB-7316	yes	6.86
E-MTAB-3929	no	877.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 28.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• Human mitochondrial F(1)F(0) ATP synthase was isolated with a one-step immunological approach. (PMID:12110673)
• Genetic variation and age are associated with skeletal muscle ATP5O mRNA expression and glucose disposal rate, suggesting that combinations of genetic and non-genetic factors may cause the reduced expression of ATP5O in type 2 diabetes muscle (PMID:19274082)
• Sirt3 physically interacted with the OSCP and led to its subsequent deacetylation. (PMID:23046812)
• Upon IF1 interaction with the ATP synthase both the synthetic and hydrolytic activities of the engine of oxidative phosphorylation are inhibited. (Review) (PMID:26876430)
• Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction. (PMID:35414767)
• A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families. (PMID:35621276)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp5po	ENSDARG00000001788
mus_musculus	Atp5po	ENSMUSG00000022956
rattus_norvegicus	Atp5po	ENSRNOG00000001991
drosophila_melanogaster	ATPsynO	FBGN0016691
caenorhabditis_elegans	atp-3	WBGENE00000230

Protein

Protein identifiers

ATP synthase peripheral stalk subunit OSCP, mitochondrial — P48047 (reviewed: P48047)

Alternative names: ATP synthase subunit O, Oligomycin sensitivity conferral protein

All UniProt accessions (6): P48047, A0A494C0K9, H7C068, H7C086, H7C239, H7C2P9

UniProt curated annotations — full annotation on UniProt →

Function. Subunit OSCP, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. ATP synthase complex consist of a soluble F(1) head domain - the catalytic core - and a membrane F(1) domain - the membrane proton channel. These two domains are linked by a central stalk rotating inside the F(1) region and a stationary peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. In vivo, can only synthesize ATP although its ATP hydrolase activity can be activated artificially in vitro. Part of the complex F(0) domain. Part of the complex F(0) domain and the peripheric stalk, which acts as a stator to hold the catalytic alpha(3)beta(3) subcomplex and subunit a/ATP6 static relative to the rotary elements.

Subunit / interactions. Component of the ATP synthase complex composed at least of ATP5F1A/subunit alpha, ATP5F1B/subunit beta, ATP5MC1/subunit c (homooctamer), MT-ATP6/subunit a, MT-ATP8/subunit 8, ATP5ME/subunit e, ATP5MF/subunit f, ATP5MG/subunit g, ATP5MK/subunit k, ATP5MJ/subunit j, ATP5F1C/subunit gamma, ATP5F1D/subunit delta, ATP5F1E/subunit epsilon, ATP5PF/subunit F6, ATP5PB/subunit b, ATP5PD/subunit d, ATP5PO/subunit OSCP. ATP synthase complex consists of a soluble F(1) head domain (subunits alpha(3) and beta(3)) - the catalytic core - and a membrane F(0) domain - the membrane proton channel (subunits c, a, 8, e, f, g, k and j). These two domains are linked by a central stalk (subunits gamma, delta, and epsilon) rotating inside the F1 region and a stationary peripheral stalk (subunits F6, b, d, and OSCP).

Subcellular location. Mitochondrion. Mitochondrion inner membrane.

Post-translational modifications. Acetylation at Lys-162 decreases ATP production. Deacetylated by SIRT3. In response to mitochondrial stress, the precursor protein is ubiquitinated by the SIFI complex in the cytoplasm before mitochondrial import, leading to its degradation. Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1.

Disease relevance. Mitochondrial complex V deficiency, nuclear type 7 (MC5DN7) [MIM:620359] An autosomal recessive, severe, mitochondrial disorder apparent soon after birth. It is characterized by multisystemic features that include hypotonia, developmental delay, progressive epileptic encephalopathy, progressive cerebral atrophy, white matter abnormalities on brain imaging, and hypertrophic cardiomyopathy in some patients. Death in infancy or early childhood may occur. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ATPase delta chain family.

RefSeq proteins (1): NP_001688* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000711	ATPase_OSCP/dsu	Family
IPR020781	ATPase_OSCP/d_CS	Conserved_site
IPR026015	ATP_synth_OSCP/delta_N_sf	Homologous_superfamily

Pfam: PF00213

UniProt features (33 total): modified residue 13, helix 9, strand 4, sequence variant 2, transit peptide 1, chain 1, mutagenesis site 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8H9E	ELECTRON MICROSCOPY	2.53
8H9S	ELECTRON MICROSCOPY	2.53
8H9L	ELECTRON MICROSCOPY	2.61
8H9U	ELECTRON MICROSCOPY	2.61
8H9I	ELECTRON MICROSCOPY	2.77
8H9T	ELECTRON MICROSCOPY	2.77
8KI3	ELECTRON MICROSCOPY	2.89
8H9P	ELECTRON MICROSCOPY	3.02
8H9V	ELECTRON MICROSCOPY	3.02

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48047-F1	84.24	0.40

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 (13): 162, 162, 172, 176, 192, 199, 54, 60, 70, 73, 90, 158, 158

Mutagenesis-validated functional residues (1):

Position	Phenotype
162	increased atp levels.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-163210	Formation of ATP by chemiosmotic coupling
R-HSA-8949613	Cristae formation
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 267 (showing top): MORF_DNMT1, RRAGTTGT_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MORF_ESPL1, MORF_BUB1, GOBP_RESPONSE_TO_PEPTIDE, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_RRM1, MORF_HDAC1, MORF_UBE2N, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOCC_CELL_SURFACE, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MORF_HDAC2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (7): ATP biosynthetic process (GO:0006754), proton motive force-driven ATP synthesis (GO:0015986), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), cellular response to cAMP (GO:0071320), cellular response to cytokine stimulus (GO:0071345), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (5): ATP hydrolysis activity (GO:0016887), protein-containing complex binding (GO:0044877), proton-transporting ATP synthase activity, rotational mechanism (GO:0046933), estradiol binding (GO:1903924), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), plasma membrane (GO:0005886), cell surface (GO:0009986), proton-transporting ATP synthase complex (GO:0045259), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Mitochondrial biogenesis	1
Metabolism of proteins	1
Metabolism	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proton motive force-driven ATP synthesis	2
binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
purine ribonucleotide biosynthetic process	1
purine ribonucleoside triphosphate biosynthetic process	1
ATP metabolic process	1
ATP biosynthetic process	1
mitochondrion	1
oxidative phosphorylation	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to cytokine	1
monoatomic cation transmembrane transport	1
transport	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
proton channel activity	1
ligase activity	1
steroid binding	1
cytoplasm	1
organelle inner membrane	1
mitochondrial membrane	1
membrane	1
cell periphery	1
proton-transporting two-sector ATPase complex	1
cation channel complex	1
respiratory chain complex	1
catalytic complex	1

Protein interactions and networks

STRING

3047 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP5PO	PPIF	P30405	989
ATP5PO	ATP5F1A	P25705	954
ATP5PO	PPID	Q08752	940
ATP5PO	ATP5PD	O75947	907
ATP5PO	ATP5PB	P24539	866
ATP5PO	ATP5PF	P18859	850
ATP5PO	ATP5F1B	P06576	845
ATP5PO	ATP5F1D	P30049	834
ATP5PO	ATP5F1C	P36542	811
ATP5PO	MT-ATP8	P03928	807
ATP5PO	ATP5F1E	P56381	796
ATP5PO	COX5B	P10606	783
ATP5PO	ATP5ME	P56385	759
ATP5PO	ATP5MF	P56134	756
ATP5PO	ATP5MC3	P48201	681

IntAct

303 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
ATP5PO	CEP70	psi-mi:“MI:0915”(physical association)	0.720
CEP70	ATP5PO	psi-mi:“MI:0915”(physical association)	0.720
PNMA1	ATP5PO	psi-mi:“MI:0915”(physical association)	0.670
ATP5PO	PNMA1	psi-mi:“MI:0915”(physical association)	0.670
ATP5PB	SLC19A2	psi-mi:“MI:0914”(association)	0.640
ACKR3	ATP5F1B	psi-mi:“MI:0914”(association)	0.640
ATP5PO	PPID	psi-mi:“MI:0915”(physical association)	0.600
ATP5PO	PPID	psi-mi:“MI:0407”(direct interaction)	0.600
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
KRT13	ATP5PO	psi-mi:“MI:0915”(physical association)	0.560
ATP5PO	NDC80	psi-mi:“MI:0915”(physical association)	0.560
ZBTB14	ATP5PO	psi-mi:“MI:0915”(physical association)	0.560
ATP5PO	KRT15	psi-mi:“MI:0915”(physical association)	0.560
ATP5PO	NT5C2	psi-mi:“MI:0915”(physical association)	0.560
TRIP6	ATP5PO	psi-mi:“MI:0915”(physical association)	0.560
ATP5PO	HMBOX1	psi-mi:“MI:0915”(physical association)	0.560
USHBP1	ATP5PO	psi-mi:“MI:0915”(physical association)	0.560
MIPOL1	ATP5PO	psi-mi:“MI:0915”(physical association)	0.560
ATP5PO	CCDC136	psi-mi:“MI:0915”(physical association)	0.560
ATP5PO	TFIP11	psi-mi:“MI:0915”(physical association)	0.560
KRT15	ATP5PO	psi-mi:“MI:0915”(physical association)	0.560
NT5C2	ATP5PO	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (461): KRT13 (Two-hybrid), KRT15 (Two-hybrid), TRIP6 (Two-hybrid), ZBTB14 (Two-hybrid), PNMA1 (Two-hybrid), NDC80 (Two-hybrid), NT5C2 (Two-hybrid), TFIP11 (Two-hybrid), CCDC136 (Two-hybrid), HMBOX1 (Two-hybrid), CEP70 (Two-hybrid), USHBP1 (Two-hybrid), MIPOL1 (Two-hybrid), ATP5O (Affinity Capture-MS), ATP5O (Affinity Capture-MS)

ESM2 similar proteins: A5VSE4, A6UDM4, A6WXW8, A7HT49, A9M840, A9WWS5, B0VXH3, B1MT69, B2B9A1, B2S7M6, B3EX21, B3Q748, B5ZSP0, B9JTR5, C0HK56, C0RF53, C3M9S4, O74190, O74479, P09457, P11402, P13621, P22778, P32980, P48047, P51660, P93655, P97852, Q06647, Q07300, Q13DP5, Q1MAY9, Q24439, Q2EN81, Q2YLI4, Q42687, Q57B85, Q5RD23, Q6C9B1, Q6FSD5

Diamond homologs: A1B8N7, A1U7H7, A1UR46, A3PIB6, A4WUN0, A4YKD7, A5E947, A5FZ51, A5V3X2, A5VSE4, A6UDM4, A6WXW8, A7HIY0, A7HT49, A7IH28, A8HS18, A8LJR7, A9H9A1, A9IYX2, A9M840, A9W2R4, A9WWS5, B0T339, B0UE42, B0VXH3, B1I6L7, B1LVH2, B1ZEF0, B2ICI8, B2S7M6, B3EX21, B3PQ71, B3Q748, B4RD44, B4UKF3, B5ZSP0, B6IPC9, B6JD05, B7KUA5, B8EQP8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ATP5PO	“form complex”	“ATP synthase”	binding
PPIF	“up-regulates activity”	ATP5PO	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 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
Formation of ATP by chemiosmotic coupling	5	28.6×	2e-04
Cristae formation	5	17.3×	8e-04
Mitochondrial protein import	8	13.4×	6e-05
Mitochondrial biogenesis	7	11.8×	3e-04
RHOJ GTPase cycle	5	10.0×	7e-03
Protein localization	5	9.5×	8e-03
Mitochondrial protein degradation	8	9.1×	3e-04
RHOG GTPase cycle	6	8.9×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
proton motive force-driven ATP synthesis	5	30.9×	2e-04
proton motive force-driven mitochondrial ATP synthesis	8	16.2×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	35
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
147666	GRCh37/hg19 21q22.11-22.12(chr21:34997018-36118212)x3	Pathogenic
1526710	GRCh37/hg19 21q21.3-22.13(chr21:29812033-39282854)	Pathogenic
153076	GRCh37/hg19 21q21.3-22.12(chr21:29880468-36062331)x1	Pathogenic
1804019	NM_001697.3(ATP5PO):c.329-20A>G	Pathogenic
1804024	NM_001697.3(ATP5PO):c.34C>T (p.Gln12Ter)	Pathogenic
4682977	GRCh37/hg19 21q22.11-22.3(chr21:32634806-43353470)x1	Pathogenic
625736	GRCh37/hg19 21q22.11(chr21:32589903-35359935)	Pathogenic
980231	GRCh37/hg19 21q22.11(chr21:34379096-35572731)x1	Pathogenic
151383	GRCh38/hg38 21q22.11(chr21:33361172-34048047)x1	Likely pathogenic

SpliceAI

1166 predictions. Top by Δscore:

Variant	Effect	Δscore
21:33903930:CCTA:C	donor_loss	1.0000
21:33903932:TACCT:T	donor_loss	1.0000
21:33903934:C:A	donor_loss	1.0000
21:33904020:GG:G	acceptor_gain	1.0000
21:33904021:GC:G	acceptor_loss	1.0000
21:33904022:C:CC	acceptor_gain	1.0000
21:33907334:TAC:T	donor_loss	1.0000
21:33907335:ACT:A	donor_loss	1.0000
21:33907336:CTTAC:C	donor_loss	1.0000
21:33907337:T:TA	donor_loss	1.0000
21:33907338:T:TC	donor_loss	1.0000
21:33907338:TACA:T	donor_loss	1.0000
21:33907339:A:AC	donor_gain	1.0000
21:33907339:A:AG	donor_loss	1.0000
21:33907340:C:CC	donor_gain	1.0000
21:33907340:C:CT	donor_gain	1.0000
21:33907340:CA:C	donor_gain	1.0000
21:33907340:CAG:C	donor_gain	1.0000
21:33907340:CAGAT:C	donor_gain	1.0000
21:33907449:CAAAT:C	acceptor_gain	1.0000
21:33907451:AATC:A	acceptor_loss	1.0000
21:33907453:TC:T	acceptor_loss	1.0000
21:33907454:C:CA	acceptor_loss	1.0000
21:33907454:C:CC	acceptor_gain	1.0000
21:33907455:T:G	acceptor_loss	1.0000
21:33909080:A:AC	donor_gain	1.0000
21:33909081:C:CT	donor_gain	1.0000
21:33909081:CT:C	donor_gain	1.0000
21:33909081:CTG:C	donor_gain	1.0000
21:33909081:CTGA:C	donor_gain	1.0000

AlphaMissense

1365 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:33907361:A:G	C141R	0.996
21:33907432:C:G	R117P	0.996
21:33912351:A:C	Y46D	0.996
21:33912362:G:T	A42D	0.996
21:33907359:G:C	C141W	0.995
21:33907375:C:G	R136P	0.995
21:33907398:A:C	F128L	0.995
21:33907398:A:T	F128L	0.995
21:33907400:A:G	F128L	0.995
21:33909087:A:G	L108P	0.995
21:33912341:G:T	A49E	0.995
21:33912342:C:G	A49P	0.995
21:33907399:A:G	F128S	0.994
21:33903608:A:T	V187E	0.993
21:33907354:A:T	V143E	0.993
21:33907445:C:G	A113P	0.993
21:33903578:G:A	S197F	0.992
21:33912353:A:G	L45P	0.992
21:33912356:G:T	A44D	0.992
21:33907447:A:G	L112P	0.991
21:33903587:A:T	V194D	0.990
21:33912353:A:T	L45H	0.990
21:33912366:A:G	Y41H	0.990
21:33903585:C:G	D195H	0.989
21:33903981:A:G	L161P	0.989
21:33912345:C:G	A48P	0.989
21:33912372:C:G	G39R	0.989
21:33912363:C:G	A42P	0.988
21:33903993:A:G	L157S	0.987
21:33907360:C:T	C141Y	0.987

dbSNP variants (sampled 300 via entrez): RS1000107035 (21:33910598 T>C), RS1000454275 (21:33916608 G>A,C,T), RS1000575604 (21:33916903 C>A), RS1000581553 (21:33911910 T>C), RS1000587397 (21:33905875 G>A), RS1000967266 (21:33912368 C>A,G,T), RS1000979455 (21:33906134 C>A,T), RS1001240191 (21:33906007 C>G), RS1001449032 (21:33915985 T>C,G), RS1001632330 (21:33916035 G>A,C), RS1001925269 (21:33911568 T>C), RS1002272233 (21:33905375 T>C), RS1002302531 (21:33911701 T>G), RS1002377684 (21:33911299 T>C), RS1002448486 (21:33911668 T>TTTTG)

Disease associations

OMIM: gene MIM:600828 | disease phenotypes: MIM:615530, MIM:617389, MIM:105400, MIM:614104, MIM:614889, MIM:601399, MIM:620359, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex V (ATP synthase) deficiency, nuclear type 7	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 (9): early-onset Parkinson disease 20 (MONDO:0014233), developmental and epileptic encephalopathy, 53 (MONDO:0033362), amyotrophic lateral sclerosis type 1 (MONDO:0007103), DYRK1A-related intellectual disability syndrome (MONDO:0013578), immunodeficiency 28 (MONDO:0013953), hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (MONDO:0100083), microcephaly (MONDO:0001149), mitochondrial complex V (ATP synthase) deficiency, nuclear type 7 (MONDO:0957255), Leigh syndrome (MONDO:0009723)

Orphanet (7): Atypical juvenile parkinsonism (Orphanet:391411), Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency (Orphanet:319547), Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency (Orphanet:319574), DYRK1A-related intellectual disability syndrome (Orphanet:464306), Familial platelet disorder with associated myeloid malignancy (Orphanet:71290), Amyotrophic lateral sclerosis (Orphanet:803), Leigh syndrome (Orphanet:506)

HPO phenotypes

11 total (12 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0002490	Increased CSF lactate
HP:0003623	Neonatal onset
HP:0005484	Secondary microcephaly
HP:0007359	Focal-onset seizure
HP:0012444	Brain atrophy
HP:0032867	Refractory status epilepticus
HP:0000252	Microcephaly

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001765_27	Red blood cell traits	8.000000e-10
GCST003074_23	Cerebral amyloid deposition in APOEe4 non-carriers (PET imaging)	9.000000e-07
GCST010083_333	Hemoglobin levels	4.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004348	hematocrit
EFO:0007707	cerebral amyloid deposition measurement
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
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
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C531617	Amyotrophic lateral sclerosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066292 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.69	Kd	20.61	nM	CHEMBL5653589
7.69	ED50	20.61	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 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	2147921: Binding affinity to human ATP5O incubated for 45 mins by Kinobead based pull down assay	kd	0.0206	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression, decreases expression, decreases methylation	4
chloropicrin	affects expression, decreases expression	2
Acetaminophen	decreases expression	2
Atrazine	decreases expression	2
Doxorubicin	affects expression, increases expression	2
Valproic Acid	affects expression, increases methylation	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
beta-lapachone	increases expression	1
arsenite	increases reaction, affects binding	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	decreases methylation	1
artenimol	affects binding	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
CD 437	decreases expression	1
corosolic acid	decreases expression	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Irinotecan	affects cotreatment, increases response to substance	1
Benzo(a)pyrene	increases methylation	1
Cannabidiol	affects cotreatment, increases expression	1
Leucovorin	affects cotreatment, increases response to substance	1
Cuprizone	affects cotreatment, increases expression	1
Fluorouracil	affects cotreatment, increases response to substance	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Isoniazid	increases 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
CHEMBL5650963	Binding	Binding affinity to human ATP5O 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)

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

Trial	Phase	Status	Title
NCT03204500	PHASE2	COMPLETED	Dual Treatment With Lithium and Valproate in ALS.
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
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT01459302	Not specified	WITHDRAWN	Genetic Study of Familial and Sporadic ALS/Motor Neuron Disease, Miyoshi Myopathy and Other Neuromuscular Disorders
NCT03449212	Not specified	SUSPENDED	SOD1 Kinetics Measurements in ALS Patients
NCT05928416	Not specified	ACTIVE_NOT_RECRUITING	ALS Diagnosis From a Saliva Sample: a Non-coding RNA Analysis Approach
NCT07170501	Not specified	COMPLETED	Postural Control as a Predictor of Disability, Fall-Related Fear, and Social Participation in Elderly Women With Non-Specific Low Back Pain
NCT03854318	Not specified	RECRUITING	Longitudinal Studies of Patient With FPDMM
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells