ATP5F1D
protein-codingATP synthase F1 subunit delta, 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 consists of three main subunits (a, b, c). This gene encodes the delta subunit of the catalytic core. Alternatively spliced transcript variants encoding the same isoform have been identified. [provided by RefSeq, Jul 2008]
- ATP5D
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014471
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0020858
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0020858
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0020858
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *ATP5F1D* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 9, 2026. The *ATP5F1D* gene encodes the ATP synthase F(1) subunit delta, a subunit of oxidative phosphorylation complex V. The first and only report of the *ATP5F1D* gene in relation to autosomal recessive primary mitochondrial disease was in 2018 (PMID: 29478781). *ATP5F1D* has been associated with a single disease entity to date; mitochondrial complex V (ATP synthase) deficiency [OMIM# 618120]. 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 two homozygous missense variants identified in two unrelated cases from one publication (PMID: 29478781). Clinical features in affected individuals include metabolic decompensation, dilated cardiomyopathy, myopathy, developmental delay, seizures, short stature, metabolic acidosis, and lactic acidosis. Complex V deficiency was noted in skin fibroblasts. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416) and *Drosophila melanogaster* model (PMID: 29478781). 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).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATP5F1D variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001687.5. 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 | 42 | 3 | 46 | ||
| missense | 2 | 79 | 6 | 1 | 88 | |
| nonsense | 4 | 4 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 2 | 0 | 86 | 48 | 4 | 140 |
Highest pathogenic variant AF is 0.0000021535418
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001678.1 | 4 | MANE Select | |
| Ensembl | ENSP00000215375.1 | 4 | MANE Select | |
| RefSeq | NP_001001975.1 | 4 | Standard | |
| Ensembl | ENSP00000378995.1 | 4 | 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
- oxidative phosphorylation
- ATP biosynthetic process
- ATP synthesis coupled proton transport
- cristae formation
- mitochondrial ATP synthesis coupled proton transport
Molecular Function
- transporter activity
- ATP binding
- ATPase activity
- transmembrane transporter activity
- ADP binding
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
- ENST00000215375
- Coding exons
- 4
- Length
- 3076
- Individuals with no LoFs
- 124281
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 124283
- p
- 0.00000805
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.420 | 82 | 93.4 | 0.878 | 0.00000586 | 1017 |
| Missense (PolyPhen) | 29 | 32.97 | 0.87958 | 330 | ||
| Synonymous | 0.451 | 45 | 49.0 | 0.918 | 0.00000377 | 375 |
| Loss of Function | 0.975 | 2 | 4.14 | 0.483 | 1.76e-7 | 54 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000064 | 0.000063 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000090 | 0.0000089 | 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 turnover 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(1) domain and of the central stalk which is part of the complex rotary element. 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.;
Recessive Scores
- pRec
- 0.145
Intolerance Scores
- RVIS EVS
- -0.32
- RVIS percentile EVS
- 31.46
Essentials
- Essential (gene trap)
- N