ATP6AP2

Summary

ATP6AP2 (ATPase H+ transporting accessory protein 2, HGNC:18305) is a protein-coding gene on chromosome Xp11.4, encoding Renin receptor (O75787). Multifunctional protein which functions as a renin, prorenin cellular receptor and is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system. It is a selective cancer dependency (DepMap: 88.9% of cell lines).

This gene encodes a protein that is associated with adenosine triphosphatases (ATPases). Proton-translocating ATPases have fundamental roles in energy conservation, secondary active transport, acidification of intracellular compartments, and cellular pH homeostasis. There are three classes of ATPases- F, P, and V. The vacuolar (V-type) ATPases have a transmembrane proton-conducting sector and an extramembrane catalytic sector. The encoded protein has been found associated with the transmembrane sector of the V-type ATPases.

Source: NCBI Gene 10159 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ATP6AP2-related disorder (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 366 total — 8 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 77
• Cancer dependency (DepMap): dependent in 88.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005765

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18305
Approved symbol	ATP6AP2
Name	ATPase H+ transporting accessory protein 2
Location	Xp11.4
Locus type	gene with protein product
Status	Approved
Aliases	PRR, M8-9, RENR, (P)RR, APT6M8-9, ATP6M8-9
Ensembl gene	ENSG00000182220
Ensembl biotype	protein_coding
OMIM	300556
Entrez	10159

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 25 protein_coding, 9 retained_intron, 6 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000378438, ENST00000423649, ENST00000436783, ENST00000447485, ENST00000479120, ENST00000486558, ENST00000487051, ENST00000635734, ENST00000635774, ENST00000635829, ENST00000636196, ENST00000636223, ENST00000636251, ENST00000636287, ENST00000636409, ENST00000636574, ENST00000636580, ENST00000636639, ENST00000636787, ENST00000636970, ENST00000637019, ENST00000637140, ENST00000637165, ENST00000637327, ENST00000637482, ENST00000637526, ENST00000637614, ENST00000637793, ENST00000637930, ENST00000637954, ENST00000637955, ENST00000638046, ENST00000638153, ENST00000901375, ENST00000901376, ENST00000901377, ENST00000931716, ENST00000972161, ENST00000972162, ENST00000972163, ENST00000972164

RefSeq mRNA: 1 — MANE Select: NM_005765 NM_005765

CCDS: CCDS14252

Canonical transcript exons

ENST00000636580 — 9 exons

Exon	Start	End
ENSE00001305175	40588986	40589116
ENSE00001330673	40597249	40597344
ENSE00003512149	40591234	40591365
ENSE00003547465	40598681	40598734
ENSE00003577587	40597527	40597664
ENSE00003642226	40599592	40599741
ENSE00003665556	40600762	40600881
ENSE00003795548	40605561	40606848
ENSE00003798752	40580970	40581102

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 114.5132 / max 1589.1469, expressed in 1826 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195994	113.0162	1826
195995	1.2508	468
195996	0.2462	94

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
visceral pleura	UBERON:0002401	99.70	gold quality
tibia	UBERON:0000979	99.69	gold quality
germinal epithelium of ovary	UBERON:0001304	99.65	gold quality
parietal pleura	UBERON:0002400	99.60	gold quality
pleura	UBERON:0000977	99.54	gold quality
epithelium of nasopharynx	UBERON:0001951	99.53	gold quality
pigmented layer of retina	UBERON:0001782	99.50	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.48	gold quality
adult organism	UBERON:0007023	99.37	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.33	gold quality
orbitofrontal cortex	UBERON:0004167	99.33	gold quality
renal medulla	UBERON:0000362	99.32	gold quality
esophagus squamous epithelium	UBERON:0006920	99.32	gold quality
pons	UBERON:0000988	99.27	gold quality
choroid plexus epithelium	UBERON:0003911	99.27	gold quality
bronchial epithelial cell	CL:0002328	99.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.26	gold quality
type B pancreatic cell	CL:0000169	99.24	gold quality
seminal vesicle	UBERON:0000998	99.23	gold quality
jejunal mucosa	UBERON:0000399	99.22	gold quality
trigeminal ganglion	UBERON:0001675	99.22	gold quality
oral cavity	UBERON:0000167	99.20	gold quality
dorsal root ganglion	UBERON:0000044	99.16	gold quality
penis	UBERON:0000989	99.16	gold quality
superior vestibular nucleus	UBERON:0007227	99.16	gold quality
parietal lobe	UBERON:0001872	99.12	gold quality
synovial joint	UBERON:0002217	99.12	gold quality
postcentral gyrus	UBERON:0002581	99.10	gold quality
superior frontal gyrus	UBERON:0002661	99.06	gold quality
urethra	UBERON:0000057	99.04	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-79	yes	2410.12
E-MTAB-6701	yes	47.73
E-HCAD-13	yes	11.78
E-CURD-114	yes	10.31
E-MTAB-10042	yes	9.51
E-HCAD-11	yes	7.20
E-MTAB-7052	no	530.28
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): VDR

miRNA regulators (miRDB)

50 targeting ATP6AP2, 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-6798-5P	100.00	65.77	699
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4269	99.55	69.89	1373

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 88.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• expression cloning of the human renin receptor complementary DNA encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein (PMID:12045255)
• specific role for the in cognitive functions and brain development (PMID:15746149)
• Renin receptor overexpression has resulted in increased intraadrenal angiotensin II, thereby provoking enhanced aldosterone generation in the absence of changes in plasma renin. (PMID:16401765)
• Human prorenin receptor directly or indirectly contributes to the regulation of renal cortical COX-2 expression. (PMID:16807542)
• existence of a novel signal transduction pathway involving the ligand renin, renin receptor, and the transcription factor PLZF (PMID:17082479)
• evidence for the AngII-independent MAPK activation by human (pro)renin receptor and induction of glomerulosclerosis with increased TGF-beta1 expression (PMID:17494887)
• equal ligand activities of both, renin and prorenin, on the (pro)renin receptor - promyelocytic zinc finger protein-phosphatidylinositol-3 kinase-p85alpha pathway (PMID:18698213)
• polymorphism of the renin receptor gene is associated with ambulatory blood pressure in Japanese men (PMID:19131936)
• prorenin, renin and the peptides bind to (P)RR and the decoy reduces prorenin binding, supporting our hypothesis that decoy peptide region has a crucial role in prorenin binding. (PMID:19513539)
• Demonstrate that the (pro)renin receptor (PRR) is expressed in retinal pigment epithelium and may have a role in hypertensive exacerbation of dry age-related macular degeneration. (PMID:19580809)
• (Pro)renin receptor may contribute to the generation of arterial angiotensin II in kidney failure patients (PMID:19641301)
• prospective crucial regions in renin and prorenin responsible for their interaction with the (pro)renin receptor [PRR] were investigated using various kinds of peptides (PMID:19733264)
• results reveal an unsuspected role for the prorenin receptor, V-ATPase activity, and acidification during Wnt/beta-catenin signaling (PMID:20093472)
• Expression of (pro)renin receptor in human kidneys with end-stage kidney disease due to diabetic nephropathy (PMID:20385187)
• Decidual prorenin may be involved in the labour-associated increase in amnion PGHS-2 abundance via the (pro)renin receptor. (PMID:20702505)
• The polymorphism of the (P)RR gene +1513A>G is associated with lacunar infarction and left ventricular hypertrophy in Japanese women. These results suggest that (P)RR has a role in organ damage in humans (PMID:21228785)
• Prorenin receptor is mainly localized in the subcellular organelles, such as the endoplasmic reticulum and Golgi apparatus, and the prorenin receptor is cleaved by ADAM19 in the Golgi, resulting in two fragments. (PMID:21270819)
• Report expression (pro)renin receptors and angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in human aortic valve stenosis. (PMID:21316680)
• that (P)RR influences blood pressure regulation in Caucasian men, potentially through altered aldosterone release (PMID:21346687)
• the crystal structure of the PRR-IC domain as maltose-binding protein (MBP) fusion proteins at 2.0A (maltose-free) and 2.15A (maltose-bound) was reported. (PMID:21420935)
• (P)RR gene activity may be controlled by intracellular AngII. (PMID:21997900)
• Angiotensin generation depending on prorenin-(P)RR interaction may occur in transgenic rodents overexpressing prorenin several 100-fold. (PMID:22025376)
• Report the presence of prorenin receptor in human substantia nigra. (PMID:22407459)
• Pro)renin receptor and insulin resistance: possible roles of angiotensin II-dependent and -independent pathways. [review] (PMID:22684035)
• Prorenin is a chemotactic factor for human aortic smooth muscle cells expressing prorenin receptor. (PMID:22721990)
• The expression of (P)RR in erythroid cells, raising the possibility that (P)RR may have a role in erythropoiesis and the pathophysiology of certain types of anemia. (PMID:22884881)
• Our data using human samples provide the first evidence that prorenin receptor is associated with angiogenic activity in proliferative diabetic retinopathy. (PMID:22930161)
• Data indicate that high circulating levels of s(P)RR at early pregnancy predicted a subsequent elevation in blood pressure, and high concentrations at delivery were significantly associated with preeclampsia. (PMID:23045457)
• These in vitro data indicate that prorenin acidified in vivo possibly modulate renin angiotensin system in (pro)renin receptor-dependent and/or -independent manners which could ultimately lead to the pathogenesis of diseases. (PMID:23111329)
• The(pro)renin receptor mediates EGF receptor transactivation in both Ang II-dependent and -independent pathways. (PMID:23277024)
• High s(P)RR concentration is associated with a lower SGA birth likelihood. (PMID:23555874)
• Results show that reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function and may ultimately be responsible for the pathology. (PMID:23595882)
• Plasma levels of prorenin receptor are increased in heart failure patients with renal dysfunction. (PMID:23673200)
• Plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity. (PMID:24218434)
• The extracellular domain (ECD) and transmembrane domain (TM) of ATP6AP2 were indispensable for the biogenesis of active V-ATPase. (PMID:24223829)
• Studies indicated that various polymorphisms in the (P)RR/ATP6ap2 gene associated with increased cardiovascular risks. (PMID:24400720)
• The aim of this study was to analyse the contribution of constitutive (P)RR activity to its cellular effects and the relevance of prorenin glycosylation on its ligand activity. (PMID:24424509)
• This study demonstrates that the the extracellular domain of ATP6AP2 participates in dimerization. (PMID:24472541)
• The binding of prorenin to PRR can promote proliferation and upregulate the anti-apoptotic protein Bcl-2 and downregulate the pro-apoptotic protein Bax independently (PMID:24591529)
• Demonstrate that there are strong interactions between prorenin, ATP6AP2, and TGFB1 and that this system has a greater capacity in female amnion to stimulate profibrotic pathways, thus maintaining the integrity of the fetal membranes. (PMID:25491485)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp6ap2	ENSDARG00000008735
mus_musculus	Atp6ap2	ENSMUSG00000031007
rattus_norvegicus	Atp6ap2	ENSRNOG00000003858
drosophila_melanogaster	ATP6AP2	FBGN0037671
caenorhabditis_elegans		WBGENE00010993
caenorhabditis_elegans		WBGENE00020500

Protein

Protein identifiers

Renin receptor — O75787 (reviewed: O75787)

Alternative names: ATPase H(+)-transporting lysosomal accessory protein 2, ATPase H(+)-transporting lysosomal-interacting protein 2, ER-localized type I transmembrane adapter, Embryonic liver differentiation factor 10, N14F, Renin/prorenin receptor, Vacuolar ATP synthase membrane sector-associated protein M8-9

All UniProt accessions (22): O75787, A0A1B0GTB0, A0A1B0GTD6, A0A1B0GTU8, A0A1B0GU12, A0A1B0GUT7, A0A1B0GUV3, A0A1B0GV24, A0A1B0GV60, A0A1B0GVB9, A0A1B0GVC7, A0A1B0GVI9, A0A1B0GVW0, A0A1B0GVZ1, A0A1B0GW13, A0A1B0GWD6, A0A1B0GWJ8, A0A1C7CYW4, B7Z1I9, B7Z413, H7C240, H7C3E1

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional protein which functions as a renin, prorenin cellular receptor and is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system. May mediate renin-dependent cellular responses by activating ERK1 and ERK2. By increasing the catalytic efficiency of renin in AGT/angiotensinogen conversion to angiotensin I, may also play a role in the renin-angiotensin system (RAS). Through its function in V-type ATPase (v-ATPase) assembly and acidification of the lysosome it regulates protein degradation and may control different signaling pathways important for proper brain development, synapse morphology and synaptic transmission.

Subunit / interactions. Interacts with renin. Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump. Interacts (via N-terminus) with ATP6AP1 (via N-terminus). Interacts with ATP6V0D1; ATP6V0D1 is a V-ATPase complex subunit and the interaction promotes V-ATPase complex assembly. Interacts with TMEM9; TMEM9 is a V-ATPase assembly regulator and the interaction induces the interaction with ATP6V0D1. Interacts with VMA21 (via N-terminus); VMA21 is a V-ATPase accessory component.

Subcellular location. Endoplasmic reticulum membrane. Lysosome membrane. Cytoplasmic vesicle. Autophagosome membrane. Cell projection. Dendritic spine membrane. Axon. Endosome membrane. Clathrin-coated vesicle membrane. Secretory vesicle. Synaptic vesicle membrane.

Tissue specificity. Expressed in brain, heart, placenta, liver, kidney and pancreas. Barely detectable in lung and skeletal muscles. In the kidney cortex it is restricted to the mesangium of glomeruli. In the coronary and kidney artery it is expressed in the subendothelium, associated to smooth muscles where it colocalizes with REN. Expressed in vascular structures and by syncytiotrophoblast cells in the mature fetal placenta.

Post-translational modifications. Phosphorylated. Proteolytically cleaved by a furin-like convertase in the trans-Golgi network to generate N- and C-terminal fragments.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Hedera type (MRXSH) [MIM:300423] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSH patients manifest mild to moderate intellectual disability associated with epilepsy, delays in motor milestones and speech acquisition in infancy. The disease is caused by variants affecting the gene represented in this entry. Parkinsonism with spasticity, X-linked (XPDS) [MIM:300911] A syndrome characterized by parkinsonian features, such as cogwheel rigidity, resting tremor and bradykinesia, and variably penetrant spasticity. The disease is caused by variants affecting the gene represented in this entry. Congenital disorder of glycosylation 2R (CDG2R) [MIM:301045] A form of congenital disorder of glycosylation, a genetically heterogeneous group of multisystem disorders caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. CDG2R is an X-linked recessive disorder characterized by infantile onset of liver failure, recurrent infections due to hypogammaglobulinemia, and cutis laxa. Some patients may also have mild intellectual impairment and dysmorphic features. The disease is caused by variants affecting the gene represented in this entry. Defects in ATP6AP2 may be involved in a glycosylation disorder with autophagic defects characterized by serum protein hypoglycosylation, immunodeficiency, liver disease, psychomotor impairment, and cutis laxa.

Isoforms (2)

UniProt ID	Names	Canonical?
O75787-1	1	yes
O75787-2	2

RefSeq proteins (1): NP_005756* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012493	Renin_rcpt	Family
IPR056780	Renin_r_C	Domain
IPR057318	RENR_N	Domain

Pfam: PF07850, PF25294

UniProt features (25 total): sequence conflict 5, sequence variant 4, chain 3, mutagenesis site 2, helix 2, topological domain 2, site 2, signal peptide 1, splice variant 1, turn 1, transmembrane region 1, short sequence motif 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3LC8	X-RAY DIFFRACTION	2
3LBS	X-RAY DIFFRACTION	2.15
6WLW	ELECTRON MICROSCOPY	3
9DET	ELECTRON MICROSCOPY	3
6WM2	ELECTRON MICROSCOPY	3.1
6WM3	ELECTRON MICROSCOPY	3.4
9CF8	ELECTRON MICROSCOPY	3.46
9CFC	ELECTRON MICROSCOPY	3.47
6WM4	ELECTRON MICROSCOPY	3.6
7U4T	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75787-F1	79.27	0.17

Functional residue map

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

Catalytic / active sites (2): 275–276 (cleavage; by furin-like protease); 277–278 (cleavage; by furin-like protease)

Mutagenesis-validated functional residues (2):

Position	Phenotype
346	increases cleavage and stability enhancing localization to the golgi; when associated with q-348.
348	increases cleavage and stability and enhancing localization to the golgi; when associated with q-346.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins
R-HSA-6798695	Neutrophil degranulation
R-HSA-9857377	Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy

MSigDB gene sets: 470 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, REACTOME_INNATE_IMMUNE_SYSTEM, MORF_MBD4, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_ENDOSOME_ORGANIZATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_VACUOLE_ORGANIZATION, MORF_RAB5A, RORA1_01, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION

GO Biological Process (16): angiotensin maturation (GO:0002003), vacuolar acidification (GO:0007035), lysosomal lumen acidification (GO:0007042), central nervous system maturation (GO:0021626), rostrocaudal neural tube patterning (GO:0021903), positive regulation of Wnt signaling pathway (GO:0030177), positive regulation of transforming growth factor beta1 production (GO:0032914), regulation of MAPK cascade (GO:0043408), eye pigmentation (GO:0048069), endosomal lumen acidification (GO:0048388), intracellular pH reduction (GO:0051452), head morphogenesis (GO:0060323), Golgi lumen acidification (GO:0061795), positive regulation of canonical Wnt signaling pathway (GO:0090263), synaptic vesicle lumen acidification (GO:0097401), proton transmembrane transport (GO:1902600)

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (27): Golgi membrane (GO:0000139), vacuolar proton-transporting V-type ATPase, V0 domain (GO:0000220), autophagosome membrane (GO:0000421), lysosome (GO:0005764), lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), endosome membrane (GO:0010008), membrane (GO:0016020), vacuolar proton-transporting V-type ATPase complex (GO:0016471), axon (GO:0030424), clathrin-coated vesicle membrane (GO:0030665), synaptic vesicle membrane (GO:0030672), dendritic spine membrane (GO:0032591), proton-transporting V-type ATPase complex (GO:0033176), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), ficolin-1-rich granule membrane (GO:0101003), cytoplasm (GO:0005737), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211), bounding membrane of organelle (GO:0098588)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Peptide hormone metabolism	1
Innate Immune System	1
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular pH reduction	3
vacuolar membrane	3
bounding membrane of organelle	2
cellular anatomical structure	2
secretory granule membrane	2
tertiary granule	2
regulation of angiotensin levels in blood	1
peptide hormone processing	1
vacuolar acidification	1
central nervous system development	1
anatomical structure maturation	1
anterior/posterior pattern specification	1
neural tube patterning	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
transforming growth factor beta1 production	1
regulation of transforming growth factor beta1 production	1
positive regulation of transforming growth factor beta production	1
MAPK cascade	1
regulation of intracellular signal transduction	1
developmental pigmentation	1
endosome organization	1
regulation of intracellular pH	1
anatomical structure morphogenesis	1
body morphogenesis	1
head development	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
intercellular transport	1
synaptic vesicle maturation	1
establishment of localization in cell	1
neuron cellular homeostasis	1
synaptic vesicle cycle	1
proton transmembrane transport	1
monoatomic cation transmembrane transport	1
molecular transducer activity	1
binding	1
Golgi apparatus	1

Protein interactions and networks

STRING

1670 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6AP2	REN	P00797	999
ATP6AP2	ATP6V0D1	P12953	958
ATP6AP2	AGT	P01019	917
ATP6AP2	ATP6V0E1	O15342	897
ATP6AP2	ATP6AP1	Q15904	879
ATP6AP2	ATP6V0B	Q99437	764
ATP6AP2	ENTPD2	Q9Y5L3	760
ATP6AP2	ACE2	Q9BYF1	743
ATP6AP2	ACE	P12821	723
ATP6AP2	AGTR1	P30556	716
ATP6AP2	CMA1	P23946	678
ATP6AP2	ATP6V1A	P38606	665
ATP6AP2	ATP6V1C1	P21283	631
ATP6AP2	ZBTB16	Q05516	629
ATP6AP2	ATP6V0C	P27449	625

IntAct

144 interactions, top by confidence:

A	B	Type	Score
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
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UPK2	ATP6AP2	psi-mi:“MI:0915”(physical association)	0.670
VMA12	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
TCIRG1	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
ATP6AP2	TIMMDC1	psi-mi:“MI:0915”(physical association)	0.560
TMEM203	ATP6AP2	psi-mi:“MI:0915”(physical association)	0.560
NKG7	ATP6AP2	psi-mi:“MI:0915”(physical association)	0.560
CD72	ATP6AP2	psi-mi:“MI:0915”(physical association)	0.560
ATP6AP2	SEC22A	psi-mi:“MI:0915”(physical association)	0.560
ATP6AP2	PTTG1IP	psi-mi:“MI:0915”(physical association)	0.560
ATP6AP2	NSG1	psi-mi:“MI:0915”(physical association)	0.560
ATP6AP2	TMEM203	psi-mi:“MI:0915”(physical association)	0.560
ATP6AP2	VAMP5	psi-mi:“MI:0915”(physical association)	0.560
ATP6AP2	NKG7	psi-mi:“MI:0915”(physical association)	0.560
ATP6AP2	CD72	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (422): ATP6AP2 (Affinity Capture-RNA), VMA21 (Affinity Capture-MS), TCIRG1 (Affinity Capture-MS), ATP6V0A1 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0D1 (Affinity Capture-MS), ATP6V1D (Affinity Capture-MS), ATP6V1F (Affinity Capture-MS), ATP6V1C1 (Affinity Capture-MS), ATP6AP1 (Affinity Capture-MS), PICK1 (Affinity Capture-MS), TMEM199 (Affinity Capture-MS), ATP6V0C (Affinity Capture-MS), KIAA2013 (Affinity Capture-MS), ATP6V0D2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0N6WHT4, A0A0R4IVV0, A4IH88, D4A1W8, E9Q414, F1PCT7, O08601, O75787, P02845, P04114, P05690, P06125, P18709, P18947, P18948, P25235, P55155, P55156, P55157, P55158, P81134, P87498, Q05808, Q25490, Q27309, Q2VQM5, Q2VQM6, Q3SZI6, Q3UUQ7, Q5R563, Q6AXS4, Q6DDG2, Q6RG02, Q765A7, Q7TMA5, Q7Z1M0, Q865F1, Q868N5, Q90243, Q90508

Diamond homologs: O75787, P81134, Q5R563, Q6AXS4, Q9CYN9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ATP6AP2	“form complex”	V-ATPase	binding
REN	up-regulates	ATP6AP2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 132 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	7	61.9×	8e-10
Insulin receptor recycling	11	55.1×	8e-15
Transferrin endocytosis and recycling	11	53.3×	8e-15
ROS and RNS production in phagocytes	10	44.2×	1e-12
Amino acids regulate mTORC1	7	18.4×	6e-06
Ion channel transport	12	15.2×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	8	66.3×	3e-11
vacuolar acidification	9	58.4×	1e-11
lysosomal lumen acidification	7	41.8×	4e-08
proton transmembrane transport	11	30.4×	2e-11
regulation of macroautophagy	7	18.3×	1e-05
intracellular iron ion homeostasis	5	10.8×	6e-03
smoothened signaling pathway	6	9.6×	2e-03
ERAD pathway	6	9.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	2
Uncertain significance	138
Likely benign	91
Benign	23

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
10801	NM_005765.3(ATP6AP2):c.321C>T (p.Asp107=)	Pathogenic
1526792	GRCh37/hg19 Xp11.4(chrX:40430199-41309242)	Pathogenic
3336071	NM_005765.3(ATP6AP2):c.284C>A (p.Ser95Ter)	Pathogenic
684965	GRCh37/hg19 Xp11.4(chrX:38056276-40565244)x3	Pathogenic
833473	NC_000023.10:g.(?30326313)(41000684_?)del	Pathogenic
869366	NM_005765.3(ATP6AP2):c.293T>C (p.Leu98Ser)	Pathogenic
869368	NM_005765.3(ATP6AP2):c.301-11_301-10del	Pathogenic
88756	NM_005765.3(ATP6AP2):c.345C>T (p.Ser115=)	Pathogenic
145963	GRCh38/hg38 Xp11.4(chrX:40165688-40662855)x2	Likely pathogenic
1698925	NM_005765.3(ATP6AP2):c.628G>T (p.Asp210Tyr)	Likely pathogenic

SpliceAI

1444 predictions. Top by Δscore:

Variant	Effect	Δscore
X:40581125:G:GT	donor_gain	1.0000
X:40588982:TCAGG:T	acceptor_loss	1.0000
X:40588983:CA:C	acceptor_loss	1.0000
X:40588984:A:AG	acceptor_gain	1.0000
X:40588984:AG:A	acceptor_gain	1.0000
X:40588985:G:A	acceptor_loss	1.0000
X:40588985:G:GT	acceptor_gain	1.0000
X:40588985:GG:G	acceptor_gain	1.0000
X:40588985:GGT:G	acceptor_gain	1.0000
X:40588985:GGTGT:G	acceptor_gain	1.0000
X:40589112:AAGAA:A	donor_gain	1.0000
X:40589113:AGAA:A	donor_gain	1.0000
X:40589114:G:GT	donor_gain	1.0000
X:40589114:GAA:G	donor_gain	1.0000
X:40589115:AA:A	donor_gain	1.0000
X:40589117:G:GG	donor_gain	1.0000
X:40589117:G:T	donor_loss	1.0000
X:40589118:T:A	donor_loss	1.0000
X:40591225:A:AG	acceptor_gain	1.0000
X:40591225:AAT:A	acceptor_gain	1.0000
X:40591226:A:G	acceptor_gain	1.0000
X:40591232:A:AG	acceptor_gain	1.0000
X:40591232:AG:A	acceptor_gain	1.0000
X:40591233:G:A	acceptor_loss	1.0000
X:40591233:G:GA	acceptor_gain	1.0000
X:40591233:GG:G	acceptor_gain	1.0000
X:40591233:GGA:G	acceptor_gain	1.0000
X:40591233:GGAC:G	acceptor_gain	1.0000
X:40591233:GGACC:G	acceptor_gain	1.0000
X:40591361:AGAAT:A	donor_gain	1.0000

AlphaMissense

2291 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:40605711:A:C	S337R	0.999
X:40605713:C:A	S337R	0.999
X:40605713:C:G	S337R	0.999
X:40605636:T:A	W312R	0.998
X:40605636:T:C	W312R	0.998
X:40605724:G:C	R341T	0.998
X:40605724:G:T	R341M	0.998
X:40605725:G:C	R341S	0.998
X:40605725:G:T	R341S	0.998
X:40591243:T:A	W60R	0.997
X:40591243:T:C	W60R	0.997
X:40591285:G:C	A74P	0.997
X:40605708:G:C	D336H	0.996
X:40605709:A:T	D336V	0.996
X:40605718:T:A	I339N	0.996
X:40605720:T:G	Y340D	0.996
X:40605709:A:C	D336A	0.995
X:40605712:G:T	S337I	0.995
X:40605720:T:C	Y340H	0.995
X:40591245:G:C	W60C	0.994
X:40591245:G:T	W60C	0.994
X:40591286:C:A	A74D	0.994
X:40599709:G:C	A236P	0.994
X:40605715:T:A	I338N	0.994
X:40605723:A:G	R341G	0.994
X:40599644:T:C	L214P	0.993
X:40605718:T:G	I339S	0.993
X:40597316:T:A	V123D	0.992
X:40597560:T:C	F144L	0.992
X:40597562:T:A	F144L	0.992

dbSNP variants (sampled 300 via entrez): RS1000487240 (X:40581683 A>C,T), RS1001007999 (X:40579483 C>T), RS1001032181 (X:40594020 A>G,T), RS1001081010 (X:40602649 C>A), RS1001149349 (X:40588329 T>G), RS1001279833 (X:40605087 C>T), RS1001486915 (X:40590251 A>G), RS1001517117 (X:40588732 A>G), RS1001537984 (X:40593099 T>C,G), RS1001761067 (X:40603866 G>A), RS1001792009 (X:40589441 C>A,T), RS1001825401 (X:40584282 T>C), RS1001845496 (X:40595226 G>A), RS1001874100 (X:40580330 T>C), RS1001876722 (X:40594815 A>G)

Disease associations

OMIM: gene MIM:300556 | disease phenotypes: MIM:300423, MIM:301045, MIM:300911, MIM:311250

GenCC curated gene-disease

Disease	Classification	Inheritance
ATP6AP2-related disorder	Definitive	X-linked
syndromic X-linked intellectual disability Hedera type	Strong	X-linked
X-linked parkinsonism-spasticity syndrome	Strong	X-linked
congenital disorder of glycosylation, type IIr	Strong	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ATP6AP2-related disorder	Definitive	XL

Mondo (5): syndromic X-linked intellectual disability Hedera type (MONDO:0010319), congenital disorder of glycosylation, type IIr (MONDO:0026765), X-linked parkinsonism-spasticity syndrome (MONDO:0010482), ATP6AP2-related disorder (MONDO:0100146), ornithine carbamoyltransferase deficiency (MONDO:0010703)

Orphanet (3): X-linked intellectual disability, Hedera type (Orphanet:93952), X-linked parkinsonism-spasticity syndrome (Orphanet:363654), Ornithine transcarbamylase deficiency (Orphanet:664)

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000047	Hypospadias
HP:0000298	Mask-like facies
HP:0000338	Hypomimic face
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000750	Delayed speech and language development
HP:0000952	Jaundice
HP:0000973	Cutis laxa
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001310	Dysmetria
HP:0001347	Hyperreflexia
HP:0001350	Slurred speech
HP:0001397	Hepatic steatosis
HP:0001410	Decreased liver function
HP:0001413	Micronodular cirrhosis
HP:0001419	X-linked recessive inheritance
HP:0001513	Obesity
HP:0001541	Ascites
HP:0001621	Weak voice
HP:0001712	Left ventricular hypertrophy
HP:0001763	Pes planus

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_373	Metabolite levels	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010436	triacylglycerol 56:9 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D020163	Ornithine Carbamoyltransferase Deficiency Disease	C10.228.140.163.100.937.750; C16.320.322.828; C16.320.565.100.940.750; C16.320.565.189.937.750; C18.452.132.100.937.500; C18.452.648.100.940.500; C18.452.648.189.937.500
C564516	Mental Retardation, X-Linked, with Epilepsy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects methylation, increases expression	6
sodium arsenite	increases expression, decreases expression, increases abundance	2
Cisplatin	affects response to substance, increases expression	2
Lead	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	increases expression	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression	1
trichostatin A	affects expression	1
arsenite	increases methylation	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	decreases expression	1
nivalenol	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	affects expression	1
corosolic acid	increases expression	1
nutlin 3	affects cotreatment, increases expression, increases secretion	1
ICG 001	increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KT35	HeLa SilenciX ATP6AP2	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05345171	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency
NCT00718627	PHASE2	COMPLETED	Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders
NCT01599286	PHASE2	COMPLETED	Short-Term Outcome of N-Carbamylglutamate in the Treatment of Acute Hyperammonemia
NCT05526066	PHASE2	TERMINATED	Study for Adolescents and Adults With Ornithine Transcarbamylase Deficiency to Evaluate Safety and Tolerability of ARCT-810
NCT06488313	PHASE2	RECRUITING	A Study to Evaluate the Pharmacodynamics and Safety of ARCT-810 in Participants With OTCD
NCT04416126	PHASE1	COMPLETED	Safety, Tolerability and Pharmacokinetics of ARCT-810 in Healthy Adult Subjects
NCT04442347	PHASE1	COMPLETED	Phase 1b Study to Assess Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects With Ornithine Transcarbamylase Deficiency
NCT06247670	PHASE1	ACTIVE_NOT_RECRUITING	Study of CMP-CPS-001 in Healthy Volunteers and Participants With Abnormal Heterozygous OTC Genotype
NCT02991144	PHASE1/PHASE2	COMPLETED	Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset Ornithine Transcarbamylase (OTC) Deficiency
NCT03767270	PHASE1/PHASE2	WITHDRAWN	Safety, Tolerability and PK/PD Evaluation of Intravenous Administration of MRT5201 in Patients With OTC Deficiency
NCT05092685	PHASE1/PHASE2	RECRUITING	Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn
NCT06255782	PHASE1/PHASE2	RECRUITING	An Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency
NCT00472732	Not specified	COMPLETED	Neurologic Injuries in Adults With Urea Cycle Disorders
NCT01421888	Not specified	TERMINATED	The NIH UNI Study: Urea Cycle Disorders, Nutrition and Immunity
NCT01569568	Not specified	COMPLETED	Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI
NCT03636438	Not specified	ACTIVE_NOT_RECRUITING	Long Term Follow Up to Evaluate DTX301 in Adults With Late-Onset OTC Deficiency
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04248062	Not specified	COMPLETED	Patient and Observer Reported Outcome Measurements in Inborn Errors of Metabolism
NCT04269122	Not specified	COMPLETED	A Study to Assess Plasma Ammonia Time-Normalized Area Under the Curve and Rate of Ureagenesis in Healthy Adult Subjects
NCT04612764	Not specified	ACTIVE_NOT_RECRUITING	Liver Disease in Urea Cycle Disorders
NCT04717453	Not specified	TERMINATED	Study to Characterize Rate of Ureagenesis in Patients With Ornithine Transcarbamylase (OTC) Deficiency
NCT04908319	Not specified	RECRUITING	Hepatic Histopathology in Urea Cycle Disorders
NCT04909346	Not specified	TERMINATED	Adeno-Associated Virus (AAV) Antibody Study in Subjects OTC Deficiency, GSDIa, and Wilson Disease
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT06805695	Not specified	RECRUITING	Long-term Follow-up (LTFU) Study of Participants in Any iECURE Protocol Using an Investigational Product (IP)