ATP5F1A
protein-codingATP synthase F1 subunit alpha, the group of ATPase F1/V1 alpha/A and beta/B subunit family|Mitochondrial complex V: ATP synthase subunits
Gene summary
This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, using an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the alpha subunit of the catalytic core. Alternatively spliced transcript variants encoding the different isoforms have been identified. Pseudogenes of this gene are located on chromosomes 9, 2, and 16. [provided by RefSeq, Mar 2012]
- ATP5AL2
- ATPM
- ATP5A1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0957254
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0957254
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014091
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014471
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0020727
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0957254
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATP5F1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004046.6. 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 | 3 | 55 | 3 | 61 | ||
| missense | 2 | 6 | 133 | 10 | 3 | 154 |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 7 | |||
| Total | 2 | 7 | 144 | 65 | 6 | 224 |
Highest pathogenic variant AF is 6.8406376e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004037.1 | 12 | MANE Select | |
| Ensembl | ENSP00000381736.5 | 12 | MANE Select | |
| RefSeq | NP_001001935.1 | 10 | Standard | |
| RefSeq | NP_001001937.1 | 12 | 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)
- Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics
- Oxidative phosphorylation - Homo sapiens (human)
Biological Process
- negative regulation of endothelial cell proliferation
- lipid metabolic process
- ATP biosynthetic process
- response to oxidative stress
- ATP synthesis coupled proton transport
Molecular Function
- RNA binding
- protein binding
- ATP binding
- ATPase activity
- transmembrane transporter activity
Cellular Component
- mitochondrial proton-transporting ATP synthase complex, catalytic core F(1)
- mitochondrion
- mitochondrial inner membrane
- mitochondrial proton-transporting ATP synthase complex
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000282050
- Coding exons
- 12
- Length
- 20191
- Individuals with no LoFs
- 125739
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125744
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.44 | 205 | 329 | 0.622 | 0.0000191 | 3547 |
| Missense (PolyPhen) | 52 | 156.95 | 0.33131 | 1714 | ||
| Synonymous | -0.444 | 126 | 120 | 1.05 | 0.00000678 | 1163 |
| Loss of Function | 4.55 | 1 | 26.1 | 0.0384 | 0.00000142 | 307 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
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. Subunits alpha and beta form the catalytic core in F(1). Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits. Subunit alpha does not bear the catalytic high-affinity ATP-binding sites (By similarity). {ECO:0000250, ECO:0000269|PubMed:10077593, ECO:0000269|PubMed:19285951}.;
- Disease
- DISEASE: Combined oxidative phosphorylation deficiency 22 (COXPD22) [MIM:616045]: A mitochondrial disorder characterized by intrauterine growth retardation, microcephaly, hypotonia, pulmonary hypertension, failure to thrive, encephalopathy, and heart failure. {ECO:0000269|PubMed:23596069}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial complex V deficiency, nuclear 4 (MC5DN4) [MIM:615228]: A mitochondrial disorder with heterogeneous clinical manifestations including dysmorphic features, psychomotor retardation, hypotonia, growth retardation, cardiomyopathy, enlarged liver, hypoplastic kidneys and elevated lactate levels in urine, plasma and cerebrospinal fluid. {ECO:0000269|PubMed:23599390}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.584
Intolerance Scores
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 27.88
Essentials
- Essential (gene trap)
- E