ATP5MC3
protein-codingATP synthase membrane subunit c locus 3, the group of Mitochondrial complex V: ATP synthase subunits
Gene summary
This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing 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 seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene is one of three genes that encode subunit c of the proton channel. Each of the three genes have distinct mitochondrial import sequences but encode the identical mature protein. Alternatively spliced transcript variants encoding different proteins have been identified. [provided by RefSeq, Jun 2010]
- ATP5G3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0859215
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *ATP5MC3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 9, 2026. The *ATP5MC3* gene encodes ATP synthase F(0) complex subunit C3, a component of ATP synthase (oxidative phosphorylation complex V). The *ATP5MC3* gene was first reported in relation to autosomal dominant primary mitochondrial disease in 2023 (PMID: 34636445), although the locus was first detected in a linkage study in 2009 (PMD: 19006192). *ATP5MC3* has been associated with a single disease entity to date; dystonia, early-onset, and/or spastic paraplegia [OMIM# 619681]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique missense variants identified in four unrelated cases from two publications (PMIDs: 34636445, 34954817). Clinical features in affected individuals include dystonia, spasticity, and developmental delay. Complex V activity was decreased in cultured skin fibroblasts. The mechanism of disease is unclear. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416) and a *Drosophila melanogaster* model (PMID: 34636445). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel February 9, 2026 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0859215
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: Neurologic
Rationale: Bilateral pallidal deep brain stimulation has been described as beneficial for ambulation and hand use
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATP5MC3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001689.5. 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 | 1 | 1 | 2 | |||
| missense | 2 | 1 | 18 | 3 | 24 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 2 | 1 | 21 | 4 | 1 | 29 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001680.1 | 4 | MANE Select | |
| Ensembl | ENSP00000284727.4 | 4 | MANE Select | |
| RefSeq | NP_001002258.1 | 4 | Standard | |
| RefSeq | NP_001177258.1 | 3 | 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
- ATP synthesis coupled proton transport
- ATP hydrolysis coupled proton transport
- cristae formation
Molecular Function
- transporter activity
- lipid binding
- proton-transporting ATP synthase activity, rotational mechanism
Cellular Component
- mitochondrial proton-transporting ATP synthase complex, coupling factor F(o)
- mitochondrial outer membrane
- mitochondrial proton-transporting ATP synthase complex
- integral component of membrane
- proton-transporting ATP synthase complex, coupling factor F(o)
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000284727
- Coding exons
- 4
- Length
- 8350
- Individuals with no LoFs
- 125158
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125166
- p
- 0.0000320
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.02 | 51 | 76.0 | 0.671 | 0.00000354 | 893 |
| Missense (PolyPhen) | 13 | 29.313 | 0.44349 | 362 | ||
| Synonymous | -0.489 | 32 | 28.7 | 1.12 | 0.00000141 | 303 |
| Loss of Function | 1.89 | 2 | 7.62 | 0.262 | 4.74e-7 | 78 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.000055 | 0.000053 | 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. Part of the complex F(0) domain. A homomeric c-ring of probably 10 subunits is part of the complex rotary element.;
Recessive Scores
- pRec
- 0.104
Intolerance Scores
- RVIS EVS
- -0.1
- RVIS percentile EVS
- 46.2
Essentials
- Essential (gene trap)
- N