ATP5PO

protein-coding

ATP synthase peripheral stalk subunit OSCP, the group of Mitochondrial complex V: ATP synthase subunits

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:

ATP5O

MANE transcript

NM_001697.3

Inheritance

ClinVar variants

P:2U:33B:4

Top phenotype

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr21:33,903,453-33,915,814

External References & Databases

Ensembl (ENSG00000241837)

Transcript & Mutation Effects

hg38 • Region Span ~12.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex V (ATP synthase) deficiency, nuclear type 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957255

Submitter: PanelApp Australia

mitochondrial diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *ATP5PO* and *ATP5PO*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 26, 2024. The *ATP5PO* gene encodes the oligomycin sensitivity-conferring protein (OSCP) of mitochondrial oxidative phosphorylation complex V. Defects of this protein lead to complex V deficiency. The *ATP5PO* gene was first reported in relation to autosomal recessive *ATP5PO*-related primary mitochondrial disease in 2022 (PMID: 34954817). *ATP5PO* has been associated with a single disease entity to date; mitochondrial complex V (ATP synthase) deficiency, nuclear type 7 [OMIM#620359]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *ATP5PO*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique variants (one nonsense, two variants resulting in altered splicing) identified in three unrelated cases from two publications (PMIDs: 34954817, 35621276). The age of onset was neonatal in all three cases and clinical features in affected individuals included intrauterine growth restriction, neonatal respiratory distress, seizures that developed into refractory status epilepticus, microcephaly, global developmental delay, dystonia, hypertrophic cardiomyopathy, and hydronephrosis and renal insufficiency. Cerebrospinal fluid lactate was elevated. Brain imaging showed progressive brain atrophy, periventricular cysts with mild ventriculomegaly, arachnoid cysts in the posterior fossa and left anterior-inferior temporal lobe, white matter hypersignal around the ventricles, and thin corpus callosum. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 21874297), yeast model (PMID: 35621276), and zebrafish model (PMID: 38128843). In summary, there is strong evidence to support the relationship between ATP5PO and autosomal recessive *ATP5PO*-related primary mitochondrial disease. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 26, 2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7AR

Manifestation: Biochemical; Cardiovascular; Craniofacial; Neurologic

Intervention: Cardiovascular

Rationale: The condition can include hypertrophic cardiomyopathy, and early diagnosis may enable management

Refs: 34954817; 35621276

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP5PO variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 34

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7Total: 4

not providedTotal: 2

SeizureTotal: 2

DysphagiaTotal: 2

MicrocephalyTotal: 2

ATP5PO-related disorderTotal: 2

Severe global developmental delayTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001697.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				2 clinvar		2
missense			31 clinvar	2 clinvar		33
nonsense	1 clinvar					1
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	1	33	4	0	39

Highest pathogenic variant AF is 0.000004220086

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001697.3	RefSeq	NP_001688.1	7	MANE Select
ENST00000290299.7	Ensembl	ENSP00000290299.2	7	MANE Select
ENST00000417181.5	Ensembl	ENSP00000407220.1	2	Standard
ENST00000418933.1	Ensembl	ENSP00000393211.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
atp5po	Danio rerio	Structure: anatomical system Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

atp5po

Danio rerio

Structure: anatomical system

Quality: quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)
Parkinson,s disease - Homo sapiens (human)

Biological Process

ATP biosynthetic process
cristae formation
mitochondrial ATP synthesis coupled proton transport
ATP hydrolysis coupled cation transmembrane transport
proton transmembrane transport

Molecular Function

transporter activity
protein binding
drug binding
ATPase activity
transmembrane transporter activity

Cellular Component

nucleus
mitochondrion
mitochondrial inner membrane
mitochondrial proton-transporting ATP synthase complex
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000290299
Coding exons: 7
Length: 12528
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125747
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0269	117	118	0.993	0.00000640	1347
Missense (PolyPhen)		18	25.107	0.71693		364
Synonymous	-0.479	48	44.0	1.09	0.00000233	433
Loss of Function	2.10	4	11.8	0.339	6.47e-7	139

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) 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. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core and F(0) - containing the membrane proton channel, linked together by a central stalk and a 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. 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.;

Recessive Scores

pRec: 0.300

Intolerance Scores

RVIS EVS: -0.05
RVIS percentile EVS: 50.01

Essentials

Essential (gene trap): E