ATP6V1A
protein-codingATPase H+ transporting V1 subunit A, the group of ATPase F1/V1 alpha/A and beta/B subunit family|V-type ATPase subunits
Gene summary
This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c", and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain A subunit isoforms and is found in all tissues. Transcript variants derived from alternative polyadenylation exist. [provided by RefSeq, Jul 2008]
- VPP2
- ATP6A1
- ATP6V1A1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~65.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0027451
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0027451
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0020632
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0020632
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0027451
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0027451
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0027451
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0020632
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0027451
Submitter: ClinGen
*ATP6V1A* was first reported in relation to ATP6V1A-CDG (also known as (also known as autosomal recessive cutis laxa 2D), an autosomal recessive congenital disorder of glycosylation, in 2017 (Van Damme et al, PMID: 28065471). ATP6V1A-CDG is characterized by the features of cutis laxa (wrinkly, inelastic, droopy skin), redundant skin, typical mask-like facial appearance, muscular hypotonia, cardiac abnormalities, and glycosylation and Golgi defects. Variants in ATP6V1A have been reported in individuals with the following disease entities in OMIM: Cutis laxa, autosomal recessive, type IID (MIM# 617403) and Developmental and epileptic encephalopathy 93 (MIM# 618012). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanism), phenotype, and inheritance pattern for these two disease entities. Therefore, the two disease entities have remained split. The split curation for Developmental and epileptic encephalopathy 93 (MIM# 618012) may be curated by another ClinGen GCEP. The disease entity in the current curation (Cutis laxa, autosomal recessive, type IID (MIM# 617403) will be renamed as ATP6V1A-CDG based on expert opinion and current naming convention. Five variants (4 missense, 1 nonsense) that have been reported in 5 probands in 2 publications are included in this curation (Van Damme et al, 2017, PMID: 28065471; Vogt et al, 2021, PMID: 33320377) (Genetic evidence, 3.5 points). This gene-disease relationship is also supported by experimental evidence, including the biochemical function of the gene product.  encodes the catalytic A subunit of the V1 domain of V-ATPase. Variants in genes encoding other subunits of V-ATPase (*ATP6V0A2*,* ATP6V1E1*) have been implicated in causing similar clinical features. Specifically, the clinical validity classification for ATP6V0A2 with CDG has been classified as definitive by the ClinGen CDG GCEP. In addition, studies on skin biopsy samples and cultured fibroblasts from affected individuals show disruption of vesicular trafficking and abnormalities of elastic fibers and the extracellular matrix, consistent with the connective tissue features observed in patients (Van Damme et al, 2017, PMID: 28065471) (Experimental evidence: 2.5 points) In summary, there is limited evidence supporting the relationship between* ATP6V1A* and ATP6V1A-CDG (also known as autosomal recessive cutis laxa 2D). This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on April 3, 2024 (SOP version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0020632
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018614
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009054
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Cardiovascular
Rationale: The condition can include early-onset cardiomyopathy, and awareness may allow early diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATP6V1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001690.4. 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 | 5 | 101 | 106 | |||
| missense | 13 | 15 | 204 | 6 | 238 | |
| nonsense | 4 | 4 | ||||
| start loss | 0 | |||||
| frameshift | 11 | 11 | ||||
| splice donor/acceptor (+/-2bp) | 9 | 9 | ||||
| Total | 13 | 15 | 233 | 107 | 0 | 368 |
Highest pathogenic variant AF is 0.000006816396
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001681.2 | 14 | MANE Select | |
| Ensembl | ENSP00000273398.3 | 14 | MANE Select | |
| Ensembl | ENSP00000420146.1 | 3 | Standard | |
| Ensembl | ENSP00000419294.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| atp6v1aa | Danio rerio | Structure: vH ionocyte Quality: flux abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- mTOR signaling pathway - Homo sapiens (human)
- Synaptic vesicle cycle - Homo sapiens (human)
- Phagosome - Homo sapiens (human)
- Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
- Oxidative phosphorylation - Homo sapiens (human)
Biological Process
- cellular iron ion homeostasis
- insulin receptor signaling pathway
- ATP hydrolysis coupled proton transport
- regulation of macroautophagy
- transferrin transport
Molecular Function
- ATP binding
- proton-transporting ATPase activity, rotational mechanism
Cellular Component
- lysosomal membrane
- vacuolar membrane
- cytosol
- plasma membrane
- microvillus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000273398
- Coding exons
- 14
- Length
- 65038
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125747
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.37 | 174 | 352 | 0.494 | 0.0000186 | 4039 |
| Missense (PolyPhen) | 29 | 136.16 | 0.21298 | 1574 | ||
| Synonymous | 0.214 | 112 | 115 | 0.975 | 0.00000582 | 1193 |
| Loss of Function | 4.36 | 6 | 33.0 | 0.182 | 0.00000192 | 378 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000055 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalytic subunit of the peripheral V1 complex of vacuolar ATPase. V-ATPase vacuolar ATPase is responsible for acidifying a variety of intracellular compartments in eukaryotic cells. In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633). {ECO:0000269|PubMed:28296633}.;
Recessive Scores
- pRec
- 0.237
Intolerance Scores
- LoFtool
- 0.221
- RVIS EVS
- -0.43
- RVIS percentile EVS
- 25.15
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.109
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |