MT-ATP6
protein-codingmitochondrially encoded ATP synthase membrane subunit 6, the group of Mitochondrial complex V: ATP synthase subunits|Mitochondrially encoded protein coding genes
Gene summary
Enables proton channel activity. Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in proton motive force-driven mitochondrial ATP synthesis and proton transmembrane transport. Located in mitochondrion. Part of proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Jul 2025]
- MTATP6
- RP
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~0.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0009723
Submitter: ClinGen
The relationship between MT-ATP6 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 24, 2021. The MT-ATP6 gene encodes the ATP synthase (complex V) subunit 6. Defects of this protein lead to complex V deficiency. The MT-ATP6 gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 1992 (PMID: 1550128). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 6 variants in 18 cases (2 with m.8851T>C, 1 with m.8993T>C, 9 with m.8993T>G, 4 with m.9176T>C, 1 with m.9185T>C, and 1 with m.9191T>C) from 12 publications (PMIDs: 9270604, 11245730, 17352390, 8554662, 9501263, 23206802, 7603783, 16217706, 1456751, 1550128, 7668837, 10604142). Of note, while Gene Curation SOP Version 8 maxes case level missense variant total score at 7, the Mitochondrial Disease Gene Curation Expert Panel agreed the maximum score would be 12 given that the majority of pathogenic mitochondrial DNA variants are missense variants. Variants in the MT-ATP6 gene are associated with other mitochondrial phenotypes, including Neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), axonal Charcot-Marie-Tooth disease and spinocerebellar ataxia (PMID: 30763462). Segregation information is scored as case level evidence according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interaction, expression, functional alterations in patient cells, rescue in human cells, and animal models (PMIDs: 27977873, 25613900, 19160410, 18256697, 24316278, 17855363). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 24, 2021 (SOP Version 8).
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *MT-ATP6* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 18, 2023. The MT-ATP6 gene encodes the ATP synthase (complex V) subunit 6. Defects of this protein lead to complex V deficiency. *MT-ATP6* was first reported in relation to maternally-inherited primary mitochondrial disease in 1990 in a family with variable developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy (PMID: 2137962). Other associated features have been reported over time. While various names could be given to the constellation of features seen in those with *MT-ATP6*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MT- ATP6* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *MT- ATP6* was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on May 24, 2021 (SOP v8), with a final classification of Definitive. This current curation for the association with primary mitochondrial disease includes cases with LSS. Evidence supporting the gene-disease relationship between *MT-ATP6* and primary mitochondrial disease includes case-level data and experimental data. This curation includes eight variants (m.8851T>C, m.8969G>A, m.8993T>C, m.8993T>G, m.9176T>C, m.9176T>G, m.9185T>C, m.9191T>C) in 17 probands in 15 publications (PMIDs: 1550128, 8554662, 23206802, 1456751, 9270604, 9501263, 10604142, 17352390, 11245730, 16217706, 11731285, 27812026, 25037980, 19747204, 2137962). Age of onset in affected individuals ranged from childhood to adulthood. Clinical features in affected individuals included LSS; neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP); and mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA); as well as seizures, ataxia, choreoathetosis, axonal sensorimotor neuropathy, cognitive decline, muscle weakness, ptosis, Wolff-Parkinson-White arrhythmia, nephropathy, and sensorineural hearing loss. Brain imaging was variable and ranged from normal to findings consistent with LSS. Muscle biopsies showed accumulation of subsarcolemmal mitochondria, diminished oxidative phosphorylation (OXPHOS) activity, and decreased steady state levels of complex V. Metabolic screening labs showed elevated blood and cerebrospinal fluid lactate. Heteroplasmy levels were variable in affected individuals and their healthy family members. Segregation evidence is scored as case-level data according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by known biochemical function, cybrid studies, and yeast models (PMIDs: 27977873, 19160410, 18256697, 24316278, 17855363). In summary, there is definitive evidence to support the relationship between *MT-ATP6* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on on May 18, 2023
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0010788
Submitter: Orphanet
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0017917
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014471
Submitter: Orphanet
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0010794
Submitter: G2P
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0010794
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010080
Submitter: Orphanet
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0018343
Submitter: Orphanet
Inheritance Pattern: Mitochondrial
Disease ID:MONDO:0016814
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Cardiovascular; Hematologic
Rationale: Among other manifestations, the conditions can involve transfusion-dependent anemia, and awareness may allow early management; Surveillance for cardiovascular manifestations may allow early medical interventions
Comments: In many of the allelic disorders, mtochondrial variants may involve a variety of sequelae, including cardiovascular manifestations such as cardiomyopathy
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MT-ATP6 variants in ClinVar
No annotated ClinVar phenotypes.
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript . 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 | 0 | |||||
| missense | 0 | |||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 0 | 0 | 0 | 0 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| Ensembl | ENSP00000354632.2 | 1 | Standard |
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
- aging
- ATP synthesis coupled proton transport
- cristae formation
- mitochondrial ATP synthesis coupled proton transport
Molecular Function
- protein binding
- proton transmembrane transporter activity
- ATPase activity
- transmembrane transporter activity
- proton-transporting ATP synthase activity, rotational mechanism
Cellular Component
- mitochondrial inner membrane
- mitochondrial proton-transporting ATP synthase complex
- integral component of membrane
- proton-transporting ATP synthase complex
- proton-transporting ATP synthase complex, coupling factor F(o)
dbNSFP Gene Annotations
Source:
- 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. Key component of the proton channel; it may play a direct role in the translocation of protons across the membrane.;
- Disease
- DISEASE: Neuropathy, ataxia, and retinitis pigmentosa (NARP) [MIM:551500]: A syndrome characterized by variable combination of developmental delay, psychomotor retardation, hearing loss, optic atrophy and retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy. {ECO:0000269|PubMed:2137962}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leber hereditary optic neuropathy (LHON) [MIM:535000]: A maternally inherited disease resulting in acute or subacute loss of central vision, due to optic nerve dysfunction. Cardiac conduction defects and neurological defects have also been described in some patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. {ECO:0000269|PubMed:7726182}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:17352390, ECO:0000269|PubMed:8395787, ECO:0000269|PubMed:9270604, ECO:0000269|PubMed:9501263, ECO:0000269|PubMed:9556461}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial infantile bilateral striatal necrosis (MIBSN) [MIM:500003]: Bilateral striatal necrosis is a neurological disorder resembling Leigh syndrome. {ECO:0000269|PubMed:7668837}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial complex V deficiency, mitochondrial 1 (MC5DM1) [MIM:516060]: A mitochondrial disorder with heterogeneous clinical manifestations including neuropathy, ataxia, hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy can present with negligible to extreme hypertrophy, minimal to extensive fibrosis and myocyte disarray, absent to severe left ventricular outflow tract obstruction, and distinct septal contours/morphologies with extremely varying clinical course. {ECO:0000269|PubMed:16049925, ECO:0000269|PubMed:18055910}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, lactic acidosis, and sideroblastic anemia 3 (MLASA3) [MIM:500011]: A rare mitochondrial disorder characterized by sideroblastic anemia, muscle weakness, and exercise intolerance associated with persistent lactic acidemia. Additional MLASA3 features are failure to thrive, hearing loss, epilepsy, stroke- like episodes, and severe developmental delay. {ECO:0000269|PubMed:25037980}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ataxia and polyneuropathy, adult-onset (APAO) [MIM:500010]: A mitochondrial disease characterized by ataxia, axonal sensorimotor polyneuropathy, abnormal eye movements, and dysarthria. {ECO:0000269|PubMed:16049925, ECO:0000269|PubMed:18055910}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, infantile hypertrophic (CMHI) [MIM:500006]: An infantile form of hypertrophic cardiomyopathy, a heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:19188198}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Indispensability pred.
- N
- Indispensability score
- 0.114