ATP6V0A2

Summary

ATP6V0A2 (ATPase H+ transporting V0 subunit a2, HGNC:18481) is a protein-coding gene on chromosome 12q24.31, encoding V-type proton ATPase 116 kDa subunit a 2 (Q9Y487). Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome.

Source: NCBI Gene 23545 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive cutis laxa type 2A (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 840 total — 45 pathogenic, 28 likely-pathogenic
• Phenotypes (HPO): 118
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_012463

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18481
Approved symbol	ATP6V0A2
Name	ATPase H+ transporting V0 subunit a2
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	TJ6, a2, TJ6s, TJ6M, ATP6a2, J6B7, ATP6N1D, Vph1, Stv1, a2V, RTF
Ensembl gene	ENSG00000185344
Ensembl biotype	protein_coding
OMIM	611716
Entrez	23545

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000330342, ENST00000504192, ENST00000534943, ENST00000536426, ENST00000540368, ENST00000543687, ENST00000544833, ENST00000545059, ENST00000613625, ENST00000674794, ENST00000675260, ENST00000675344, ENST00000676034, ENST00000858646

RefSeq mRNA: 1 — MANE Select: NM_012463 NM_012463

CCDS: CCDS9254

Canonical transcript exons

ENST00000330342 — 20 exons

Exon	Start	End
ENSE00001291544	123754420	123754537
ENSE00001299384	123757927	123761755
ENSE00001304009	123756815	123756986
ENSE00001314528	123751110	123751229
ENSE00001318444	123747607	123747725
ENSE00001322876	123748575	123748785
ENSE00001360488	123712353	123712682
ENSE00003476691	123744882	123744972
ENSE00003507924	123735531	123735624
ENSE00003511270	123727783	123727909
ENSE00003578916	123718623	123718701
ENSE00003584677	123744201	123744337
ENSE00003596312	123722351	123722448
ENSE00003627110	123737059	123737271
ENSE00003637280	123752283	123752402
ENSE00003656204	123733926	123734008
ENSE00003673738	123743785	123743935
ENSE00003679959	123726197	123726285
ENSE00003683602	123744597	123744784
ENSE00003688532	123724654	123724791

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 87.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.7453 / max 481.2694, expressed in 1817 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128598	19.6086	1817
128599	0.1367	31

Top tissues by expression

280 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	87.89	gold quality
sural nerve	UBERON:0015488	87.51	gold quality
stromal cell of endometrium	CL:0002255	86.97	gold quality
adrenal tissue	UBERON:0018303	86.80	gold quality
skin of abdomen	UBERON:0001416	86.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.41	gold quality
endothelial cell	CL:0000115	84.80	silver quality
body of stomach	UBERON:0001161	84.76	gold quality
zone of skin	UBERON:0000014	84.67	gold quality
mucosa of stomach	UBERON:0001199	84.57	gold quality
monocyte	CL:0000576	84.42	gold quality
mononuclear cell	CL:0000842	84.11	gold quality
leukocyte	CL:0000738	84.01	gold quality
minor salivary gland	UBERON:0001830	83.77	gold quality
upper lobe of left lung	UBERON:0008952	83.60	gold quality
stomach	UBERON:0000945	83.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.57	gold quality
tibial nerve	UBERON:0001323	83.37	gold quality
rectum	UBERON:0001052	83.28	gold quality
Brodmann (1909) area 23	UBERON:0013554	83.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.20	gold quality
colonic epithelium	UBERON:0000397	82.86	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.72	gold quality
gastrocnemius	UBERON:0001388	82.54	gold quality
ganglionic eminence	UBERON:0004023	82.42	gold quality
granulocyte	CL:0000094	82.40	gold quality
lymph node	UBERON:0000029	82.28	gold quality
small intestine	UBERON:0002108	82.26	gold quality
body of uterus	UBERON:0009853	82.26	gold quality
transverse colon	UBERON:0001157	82.15	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	16.10
E-MTAB-9067	yes	12.32
E-MTAB-9801	yes	9.05
E-ANND-3	yes	7.76
E-MTAB-5061	yes	4.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TEAD1

miRNA regulators (miRDB)

145 targeting ATP6V0A2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 29)

• RTF (Regeneration and tolerance factor), the alpha-2 isoform of the alpha subunit of vacuolar ATPase, has a role in controlling IL-1 beta secretion by regulating P2X7 activity. (PMID:15301855)
• cells were not susceptible to apoptosis when the 70-kDa RTF was present but were when the 50-kDa RTF was present; the increase in levels of the 50-kDa RTF on cells from HIV-positive individuals is important in preventing apoptosis (PMID:15358640)
• RTF is constitutively expressed at endometrial and decidual level, and its up-regulation during the secretory phase of the cycle may be relevant in mediating some immune-related aspects of uterine physiology. (PMID:15373763)
• Its role in organellar proton pumping suggests that hTJ6 function may participate in protein trafficking/processing. (PMID:16113235)
• Data suggest a role for the N-terminus domain of the a2 isoform of vacuolar ATPase in the regulation of IL-1beta pro-inflammatory cytokine production at the fetal-maternal interface. (PMID:17295899)
• Study identified loss-of-function mutations in ATP6V0A2, encoding the a2 subunit of the V-type H+ ATPase, in several families with autosomal recessive cutis laxa type II or wrinkly skin syndrome. (PMID:18157129)
• the relationship between ATP6V0A2 mutations, the glycosylation defect and the autosomal recessive cutis laxa type II phenotype is discussed [review] (PMID:19171192)
• Loss-of-function mutations in ATP6V0A2 lead to tropoelastin aggregation in the Golgi and increased apoptosis of elastogenic cells. (PMID:19321599)
• Studies indicate that mutations in the ATP6V0A2 gene were found in families with autosomal recessive cutis laxa. (PMID:19401719)
• Specific motifs of the V-ATPase a2-subunit isoform interact with catalytic and regulatory domains of ARNO. (PMID:20153292)
• Data show that the V-ATPase a2-subunit might actually be embedded into and/or closely associated with membrane phospholipids even in the absence of any obvious predicted transmembrane segments. (PMID:20669186)
• A mechanism is described by which tumor-associated macrophages mature via a nontraditional cytokine-like signal, the a2NTD peptide. (PMID:21178005)
• Mutations in the ATP6V0A2 gene is associated with autosomal recessive cutis laxa. (PMID:22773132)
• Expression of a2 vacuolar ATPase in spermatozoa is associated with semen quality and chemokine-cytokine profiles in infertile men. (PMID:23936208)
• Case Report: novel ATP6V0A2 mutations in an infant with cutis laxa. (PMID:24815019)
• The granule-associated a2V isoform has a role in maintaining a pH gradient within the cell between the cytosol and granules in neutrophils. (PMID:25877929)
• the results from this study demonstrate that the a2-subunit isoform of Vacuolar ATPase regulates Notch signaling in breast tumor cells (PMID:26418877)
• Senescence-associated impaired expression of ATP6V0A2 triggers changes in Golgi structure and glycosylation in old fibroblasts, which demonstrates a role of ATP6V0A2 in cellular senescence program. (PMID:26611489)
• In cisplatin resistant cells, shRNA mediated inhibition of V-ATPase-V0a2 enhanced sensitivity towards both cisplatin and carboplatin. (PMID:26899534)
• a2V deficiency disrupts the endolysosomal route in Notch and TGF signaling, thereby impairing mammary gland development. (PMID:27809299)
• Study shows how tumor associated a2-isoform V-ATPase can induce neutrophil migration by stimulating autocrine secretion of IL-8, suggesting a mechanism for the creation of a level of inflammation that favors cancer growth. (PMID:27845385)
• Data suggest that missense mutations in ATP6V0A2 and ATP6V0A4 that cause either cutis laxa or distal renal tubular acidosis result in enzyme subunits that are unstable, retained in endoplasmic reticulum (rather than transported to Golgi and cell membrane), and quickly degraded by proteasomes despite full glycosylation. (PMID:29311258)
• ATP6V0A2-related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype. (PMID:29952037)
• Exome sequence analysis for the proband led to the identification of novel homozygous frameshift c.2085_2088del (p.(Ser695Argfs*12)) in ATP6V0A2, within the linked region, in the two affected siblings. (PMID:30474613)
• Low ATP6V0A2 expression is associated with asthenozoospermia. (PMID:30550884)
• Cancer-associated V-ATPase induces delayed apoptosis of protumorigenic neutrophils. (PMID:31925882)
• Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families. (PMID:37119015)
• The Human Mutation K237_V238del in a Putative Lipid Binding Motif within the V-ATPase a2 Isoform Suggests a Molecular Mechanism Underlying Cutis Laxa. (PMID:38396846)
• Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with cutis laxa. (PMID:38598037)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp6v0a2a	ENSDARG00000035538
danio_rerio	atp6v0a2b	ENSDARG00000035565
mus_musculus	Atp6v0a2	ENSMUSG00000038023
drosophila_melanogaster	Vha100-3	FBGN0028669

Paralogs (3): ATP6V0A1 (ENSG00000033627), ATP6V0A4 (ENSG00000105929), TCIRG1 (ENSG00000110719)

Protein

Protein identifiers

V-type proton ATPase 116 kDa subunit a 2 — Q9Y487 (reviewed: Q9Y487)

Alternative names: Lysosomal H(+)-transporting ATPase V0 subunit a 2, TJ6, Vacuolar proton translocating ATPase 116 kDa subunit a isoform 2

All UniProt accessions (7): A0A6Q8PFU6, A0A6Q8PHG7, F5GX48, F5H5F3, F5H847, Q9Y487, Q8TBM3

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment. Essential component of the endosomal pH-sensing machinery. May play a role in maintaining the Golgi functions, such as glycosylation maturation, by controlling the Golgi pH. 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.

Subunit / interactions. V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex. The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H. The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c’’, rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR. Directly interacts with PSCD2 through its N-terminal cytosolic tail in an intra-endosomal acidification-dependent manner. Disruption of this interaction results in the inhibition of endocytosis. Interacts with SPAAR.

Subcellular location. Cell membrane. Endosome membrane.

Disease relevance. Cutis laxa, autosomal recessive, 2A (ARCL2A) [MIM:219200] A disorder characterized by an excessive congenital skin wrinkling, a large fontanelle with delayed closure, a typical facial appearance with downslanting palpebral fissures, a general connective tissue weakness, and varying degrees of growth and developmental delay and neurological abnormalities. Some affected individuals develop seizures and mental deterioration later in life, whereas the skin phenotype tends to become milder with age. At the molecular level, an abnormal glycosylation of serum proteins is observed in many cases. The disease is caused by variants affecting the gene represented in this entry. Wrinkly skin syndrome (WSS) [MIM:278250] A rare autosomal recessive disorder characterized by wrinkling of the skin of the dorsum of the hands and feet, an increased number of palmar and plantar creases, wrinkled abdominal skin, multiple musculoskeletal abnormalities, microcephaly, growth failure and developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the V-ATPase 116 kDa subunit family.

RefSeq proteins (1): NP_036595* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002490	V-ATPase_116kDa_su	Family
IPR026028	V-type_ATPase_116kDa_su_euka	Family

Pfam: PF01496

Enzyme classification (BRENDA):

• EC 7.1.2.1 — P-type H+-exporting transporter (BRENDA: 60 organisms, 15 substrates, 91 inhibitors, 73 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.161–2.8	68
VANADATE	0.05–0.064	4

UniProt features (26 total): topological domain 9, transmembrane region 8, modified residue 2, glycosylation site 2, sequence variant 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y487-F1	81.94	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 695, 700

Glycosylation sites (2): 484, 505

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-77387	Insulin receptor recycling
R-HSA-917977	Transferrin endocytosis and recycling
R-HSA-983712	Ion channel transport

MSigDB gene sets: 540 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, ELVIDGE_HYPOXIA_DN, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, MORF_FLT1, REACTOME_INNATE_IMMUNE_SYSTEM, MORF_MSH3, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, MORF_BRCA1, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, KEGG_LYSOSOME, MORF_ESR1

GO Biological Process (8): intracellular iron ion homeostasis (GO:0006879), immune response (GO:0006955), vacuolar acidification (GO:0007035), regulation of macroautophagy (GO:0016241), cellular response to increased oxygen levels (GO:0036295), Golgi lumen acidification (GO:0061795), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (3): proton-transporting ATPase activity, rotational mechanism (GO:0046961), ATPase binding (GO:0051117), protein binding (GO:0005515)

GO Cellular Component (18): Golgi membrane (GO:0000139), vacuolar proton-transporting V-type ATPase, V0 domain (GO:0000220), acrosomal vesicle (GO:0001669), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), focal adhesion (GO:0005925), endosome membrane (GO:0010008), vacuolar proton-transporting V-type ATPase complex (GO:0016471), phagocytic vesicle membrane (GO:0030670), proton-transporting V-type ATPase complex (GO:0033176), perinuclear region of cytoplasm (GO:0048471), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), sperm head-tail coupling apparatus (GO:0120212), endosome (GO:0005768), membrane (GO:0016020), proton-transporting V-type ATPase, V0 domain (GO:0033179)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	1
Signaling by Insulin receptor	1
Iron uptake and transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
sperm flagellum	3
intracellular pH reduction	2
bounding membrane of organelle	2
vacuolar membrane	2
proton-transporting V-type ATPase complex	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
immune system process	1
response to stimulus	1
regulation of autophagy	1
macroautophagy	1
response to increased oxygen levels	1
cellular response to oxygen levels	1
monoatomic cation transmembrane transport	1
transport	1
proton transmembrane transporter activity	1
ATPase-coupled monoatomic cation transmembrane transporter activity	1
ATPase activity, coupled to transmembrane movement of ions, rotational mechanism	1
enzyme binding	1
binding	1
Golgi apparatus	1
vacuolar proton-transporting V-type ATPase complex	1
proton-transporting V-type ATPase, V0 domain	1
secretory granule	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
cell-substrate junction	1
endosome	1
cytoplasmic vesicle membrane	1
endocytic vesicle membrane	1
phagocytic vesicle	1
proton-transporting two-sector ATPase complex	1
cation-transporting ATPase complex	1
ATPase complex	1
cytoplasm	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

1668 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V0A2	ALG2	Q9H553	925
ATP6V0A2	EFEMP2	O95967	905
ATP6V0A2	NR6A1	Q15406	887
ATP6V0A2	FBLN5	Q9UBX5	863
ATP6V0A2	ATP6V0D1	P12953	844
ATP6V0A2	ATP4A	P20648	830
ATP6V0A2	ATP12A	P54707	825
ATP6V0A2	ATP6V1E2	Q96A05	810
ATP6V0A2	PYCR1	P32322	808
ATP6V0A2	ATP6V1A	P38606	797
ATP6V0A2	ATP6V1B2	P21281	795
ATP6V0A2	ATP6V1B1	P15313	788
ATP6V0A2	ADAMTS2	O95450	786
ATP6V0A2	ATP6V0C	P27449	785
ATP6V0A2	ATP6V1E1	P36543	778

IntAct

156 interactions, top by confidence:

A	B	Type	Score
LAMTOR1	LAMTOR5	psi-mi:“MI:0914”(association)	0.870
MCAM	CNTN1	psi-mi:“MI:0914”(association)	0.750
ATP6V0C	ATP6AP2	psi-mi:“MI:0914”(association)	0.730
ATP6AP2	ATP6V0C	psi-mi:“MI:0914”(association)	0.730
ATP6V0A2	ATP6AP2	psi-mi:“MI:0914”(association)	0.730
BCAM	LAMA5	psi-mi:“MI:0914”(association)	0.640
VMA12	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
TCIRG1	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
CD4	CCDC85C	psi-mi:“MI:0914”(association)	0.530
FZD10	NRP1	psi-mi:“MI:0914”(association)	0.530
FAM131B	AURKA	psi-mi:“MI:0914”(association)	0.530
TMEM185A	TSPAN6	psi-mi:“MI:0914”(association)	0.530
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
MARCKSL1	NMT2	psi-mi:“MI:0914”(association)	0.530
ATP6AP2	ATP6V1C1	psi-mi:“MI:0914”(association)	0.530
SERINC2	STOM	psi-mi:“MI:0914”(association)	0.530
ATP6V1B2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
atp6v0d_human	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
TCIRG1	AP3D1	psi-mi:“MI:0914”(association)	0.530
ATP6AP2	CLGN	psi-mi:“MI:0914”(association)	0.530
ATP6V0A1	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
SLC2A1	ATP11C	psi-mi:“MI:0914”(association)	0.530
STK16	UNC119B	psi-mi:“MI:0914”(association)	0.530

BioGRID (252): ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Proximity Label-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-Western), LAMP2 (Affinity Capture-Western)

ESM2 similar proteins: A1A5G6, A7Z064, G5EEK9, G5EGP4, O13742, O97681, P00347, P00365, P04035, P09610, P10759, P13807, P15920, P16393, P17625, P20715, P23109, P25286, P30628, P32563, P37296, P38329, P54840, P57103, P70549, Q00955, Q01237, Q01290, Q01432, Q09573, Q1W675, Q29466, Q29512, Q54E04, Q5R422, Q5R6N3, Q5R9H0, Q8AVM5, Q8MJ26, Q8RWZ7

Diamond homologs: A1A5G6, B2MZD0, G5EEK9, G5EGP4, O13742, O29106, O57721, O97681, P15920, P25286, P30628, P32563, P37296, Q01290, Q13488, Q29466, Q54E04, Q57675, Q5JDS2, Q5R422, Q8AVM5, Q8RWZ7, Q8W4S4, Q920R6, Q93050, Q9HBG4, Q9I8D0, Q9SJT7, Q9UWW3, Q9UXU2, Q9Y487, Q9Z1G4, Q9YEA0, O27041, Q9HND8, O83544

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATP6V0A2	“form complex”	V-ATPase	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 202 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	9	43.8×	2e-11
Insulin receptor recycling	14	38.6×	7e-17
Transferrin endocytosis and recycling	13	34.7×	4e-15
ROS and RNS production in phagocytes	12	29.2×	7e-13
Amino acids regulate mTORC1	12	17.4×	3e-10
Ion channel transport	16	11.1×	1e-10
RHOF GTPase cycle	5	9.4×	1e-02
RHOB GTPase cycle	8	8.9×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	12	64.6×	3e-17
vacuolar acidification	11	46.3×	9e-14
lysosomal lumen acidification	7	27.1×	2e-06
proton transmembrane transport	13	23.3×	4e-12
regulation of macroautophagy	9	15.3×	2e-06
transport across blood-brain barrier	8	8.2×	8e-04
transmembrane transport	8	7.8×	1e-03
monoatomic ion transport	8	7.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

840 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	28
Uncertain significance	323
Likely benign	289
Benign	86

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074631	NM_012463.4(ATP6V0A2):c.2203C>T (p.Gln735Ter)	Pathogenic
1218839	NM_012463.4(ATP6V0A2):c.194del (p.Leu65fs)	Pathogenic
197291	NM_012463.4(ATP6V0A2):c.304C>T (p.Gln102Ter)	Pathogenic
2000140	NM_012463.4(ATP6V0A2):c.302T>A (p.Leu101Ter)	Pathogenic
2030297	NM_012463.4(ATP6V0A2):c.1926C>A (p.Tyr642Ter)	Pathogenic
2133236	NM_012463.4(ATP6V0A2):c.1945_1946del (p.Gln649fs)	Pathogenic
2137448	NM_012463.4(ATP6V0A2):c.390_397dup (p.Arg133delinsThrCysTer)	Pathogenic
2137449	NM_012463.4(ATP6V0A2):c.2015T>A (p.Leu672Ter)	Pathogenic
21494	NM_012463.4(ATP6V0A2):c.1324G>T (p.Glu442Ter)	Pathogenic
21496	NM_012463.4(ATP6V0A2):c.2176-3_2176-2del	Pathogenic
21499	NM_012463.4(ATP6V0A2):c.294+1G>A	Pathogenic
21501	NM_012463.4(ATP6V0A2):c.732-2A>G	Pathogenic
2687870	NM_012463.4(ATP6V0A2):c.2231_2255dup (p.Tyr753fs)	Pathogenic
2789345	NM_012463.4(ATP6V0A2):c.666G>A (p.Trp222Ter)	Pathogenic
2813479	NM_012463.4(ATP6V0A2):c.1604del (p.Pro535fs)	Pathogenic
2829656	NM_012463.4(ATP6V0A2):c.851del (p.Tyr283_Leu284insTer)	Pathogenic
2838924	NM_012463.4(ATP6V0A2):c.377_378del (p.Ile126fs)	Pathogenic
2840813	NM_012463.4(ATP6V0A2):c.1994T>A (p.Leu665Ter)	Pathogenic
2991081	NM_012463.4(ATP6V0A2):c.2304del (p.Asp768fs)	Pathogenic
3004981	NM_012463.4(ATP6V0A2):c.877G>T (p.Glu293Ter)	Pathogenic
3244266	NC_000012.11:g.(?124171363)(124242579_?)del	Pathogenic
3372310	NM_012463.4(ATP6V0A2):c.1236del (p.Phe412fs)	Pathogenic
3574387	NM_012463.4(ATP6V0A2):c.130del (p.Asn43_Val44insTer)	Pathogenic
3636993	NM_012463.4(ATP6V0A2):c.112C>T (p.Arg38Ter)	Pathogenic
3658823	NM_012463.4(ATP6V0A2):c.986G>A (p.Trp329Ter)	Pathogenic
3674447	NM_012463.4(ATP6V0A2):c.1519_1540dup (p.Ile514delinsLysArgArgTer)	Pathogenic
3706136	NM_012463.4(ATP6V0A2):c.913del (p.Lys304_Met305insTer)	Pathogenic
3775300	NM_012463.4(ATP6V0A2):c.1776_1777dup (p.Phe593fs)	Pathogenic
39452	NM_012463.4(ATP6V0A2):c.2356_2362del (p.Gly786fs)	Pathogenic
39453	ATP6V0A2, 1-BP INS, 100A	Pathogenic

SpliceAI

3352 predictions. Top by Δscore:

Variant	Effect	Δscore
12:123712680:GAC:G	donor_gain	1.0000
12:123712683:G:GG	donor_gain	1.0000
12:123718618:CTCA:C	acceptor_loss	1.0000
12:123718619:TCA:T	acceptor_loss	1.0000
12:123718621:A:AG	acceptor_gain	1.0000
12:123718621:AGCT:A	acceptor_loss	1.0000
12:123718622:G:GG	acceptor_gain	1.0000
12:123718622:GCT:G	acceptor_gain	1.0000
12:123718622:GCTC:G	acceptor_gain	1.0000
12:123718622:GCTCA:G	acceptor_gain	1.0000
12:123718700:GG:G	donor_gain	1.0000
12:123718700:GGGTA:G	donor_loss	1.0000
12:123718701:GG:G	donor_gain	1.0000
12:123718701:GGTAA:G	donor_loss	1.0000
12:123718702:G:GC	donor_loss	1.0000
12:123718702:G:GG	donor_gain	1.0000
12:123718703:T:G	donor_loss	1.0000
12:123722349:A:AG	acceptor_gain	1.0000
12:123722350:G:GG	acceptor_gain	1.0000
12:123722350:GT:G	acceptor_gain	1.0000
12:123724652:A:AG	acceptor_gain	1.0000
12:123724653:G:A	acceptor_loss	1.0000
12:123724653:G:GA	acceptor_gain	1.0000
12:123724653:GGA:G	acceptor_gain	1.0000
12:123724653:GGAGC:G	acceptor_gain	1.0000
12:123724787:TTG:T	donor_gain	1.0000
12:123724787:TTGAG:T	donor_loss	1.0000
12:123724788:TGAGG:T	donor_loss	1.0000
12:123724791:GGTA:G	donor_loss	1.0000
12:123724792:GTA:G	donor_loss	1.0000

AlphaMissense

5661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:123754505:T:C	L754P	1.000
12:123754513:T:A	W757R	1.000
12:123754513:T:C	W757R	1.000
12:123724712:T:C	L118P	0.999
12:123724733:T:C	L125P	0.999
12:123727794:G:A	G178D	0.999
12:123735617:T:C	L273P	0.999
12:123744717:T:A	W483R	0.999
12:123744717:T:C	W483R	0.999
12:123747610:T:A	W537R	0.999
12:123747610:T:C	W537R	0.999
12:123747654:A:C	K551N	0.999
12:123747654:A:T	K551N	0.999
12:123747656:T:C	M552T	0.999
12:123754508:G:C	R755T	0.999
12:123754508:G:T	R755M	0.999
12:123754511:T:C	L756P	0.999
12:123754515:G:C	W757C	0.999
12:123754515:G:T	W757C	0.999
12:123754522:A:C	S760R	0.999
12:123754524:C:A	S760R	0.999
12:123754524:C:G	S760R	0.999
12:123754526:T:C	L761P	0.999
12:123724682:T:C	L108P	0.998
12:123727842:G:C	R194T	0.998
12:123727843:A:C	R194S	0.998
12:123727843:A:T	R194S	0.998
12:123733990:T:A	V238D	0.998
12:123733999:T:A	I241K	0.998
12:123735596:T:C	L266P	0.998

dbSNP variants (sampled 300 via entrez): RS1000042381 (12:123758584 G>A), RS1000077114 (12:123737588 A>G,T), RS1000122159 (12:123732082 T>C), RS1000173598 (12:123737527 G>A,T), RS1000249040 (12:123718295 G>T), RS1000309309 (12:123738069 A>C,G,T), RS1000313766 (12:123719154 G>A,T), RS1000340470 (12:123750137 A>G), RS1000367544 (12:123761014 C>A,T), RS1000469789 (12:123737816 T>C), RS1000560637 (12:123742144 A>G), RS1000596965 (12:123712150 C>T), RS1000621967 (12:123748631 T>C), RS1000650180 (12:123736427 C>T), RS1000717505 (12:123761387 G>A,C)

Disease associations

OMIM: gene MIM:611716 | disease phenotypes: MIM:608776, MIM:219200, MIM:278250, MIM:213300, MIM:249000

GenCC curated gene-disease

Disease	Classification	Inheritance
wrinkly skin syndrome	Definitive	Autosomal recessive
autosomal recessive cutis laxa type 2, classic type	Strong	Autosomal recessive
autosomal recessive cutis laxa type 2A	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal recessive cutis laxa type 2A	Definitive	AR

Mondo (7): ALG9-congenital disorder of glycosylation (MONDO:0012117), autosomal recessive cutis laxa type 2A (MONDO:0018163), wrinkly skin syndrome (MONDO:0010208), cutis laxa (MONDO:0016175), Joubert syndrome (MONDO:0018772), Meckel syndrome (MONDO:0018921), autosomal recessive cutis laxa type 2, classic type (MONDO:0009054)

Orphanet (7): ALG9-CDG (Orphanet:79328), Autosomal recessive cutis laxa type 2A (Orphanet:357058), Wrinkly skin syndrome (Orphanet:2834), Cutis laxa (Orphanet:209), Isolated Joubert syndrome (Orphanet:475), Meckel syndrome (Orphanet:564), Autosomal recessive cutis laxa type 2, classic type (Orphanet:357074)

HPO phenotypes

118 total (30 of 118 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000260	Wide anterior fontanel
HP:0000270	Delayed cranial suture closure
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000545	Myopia
HP:0000592	Blue sclerae
HP:0000670	Carious teeth
HP:0000684	Delayed eruption of teeth
HP:0000691	Microdontia
HP:0000726	Dementia
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000938	Osteopenia

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST001465_13	Adiponectin levels	3.000000e-10
GCST005956_10	Waist-to-hip ratio adjusted for BMI	6.000000e-08
GCST005958_11	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-07
GCST005962_22	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-08
GCST90002398_205	Neutrophil count	7.000000e-09
GCST90020024_454	A body shape index	2.000000e-12
GCST90020024_456	A body shape index	3.000000e-12
GCST90020024_457	A body shape index	1.000000e-11
GCST90020025_57	Waist-to-hip ratio adjusted for BMI	1.000000e-17
GCST90020025_58	Waist-to-hip ratio adjusted for BMI	4.000000e-09
GCST90020025_60	Waist-to-hip ratio adjusted for BMI	2.000000e-16
GCST90020025_61	Waist-to-hip ratio adjusted for BMI	1.000000e-15
GCST90020027_1232	Waist-hip index	9.000000e-19
GCST90020027_1233	Waist-hip index	4.000000e-09
GCST90020027_1235	Waist-hip index	2.000000e-16
GCST90020027_1236	Waist-hip index	2.000000e-16
GCST90020029_254	Waist circumference adjusted for body mass index	2.000000e-15
GCST90020029_255	Waist circumference adjusted for body mass index	2.000000e-10
GCST90020029_256	Waist circumference adjusted for body mass index	9.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004502	adiponectin measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004833	neutrophil count
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D003483	Cutis Laxa	C16.320.850.180; C17.300.230; C17.800.827.180
C535750	Congenital disorder of glycosylation type 1L (supp.)
C562632	Cutis Laxa, Autosomal Recessive, Type IIA (supp.)
C536750	Wrinkly skin syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — V-type ATPase

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
FR900359	increases phosphorylation	1
TL8-506	affects cotreatment, increases expression	1
daidzein	affects cotreatment, decreases expression	1
bisphenol A	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
coumarin	affects phosphorylation	1
beta-methylcholine	affects expression	1
tamibarotene	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
glycitein	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Glyphosate	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	affects phosphorylation	1
Diazinon	increases methylation	1
Estradiol	increases expression	1
Hydroxyurea	decreases expression	1
Lead	affects expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SE17	HAP1 ATP6V0A2 (-) 1	Cancer cell line	Male
CVCL_SE18	HAP1 ATP6V0A2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

9 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03887208	PHASE1/PHASE2	COMPLETED	Therapy of Scars and Cutis Laxa With Autologous Adipose Derived Mesenchymal Stem Cells
NCT01293864	Not specified	TERMINATED	Structural Analysis of Human Tissue
NCT01658163	Not specified	COMPLETED	Use of 2-octyl-cyanoacrylate Together With a Self-adhering Mesh
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07614997	Not specified	NOT_YET_RECRUITING	Effectiveness and Safety of the Ulthera® System for Skin Laxity in the Lower Face, Submentum and Neck
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)