ATP6V1E2

Summary

ATP6V1E2 (ATPase H+ transporting V1 subunit E2, HGNC:18125) is a protein-coding gene on chromosome 2p21, encoding V-type proton ATPase subunit E 2 (Q96A05). Subunit of the V1 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.

Predicted to enable proton-transporting ATPase activity, rotational mechanism. Predicted to be involved in regulation of macroautophagy. Predicted to act upstream of or within proton transmembrane transport. Predicted to be located in cytosol. Predicted to be part of proton-transporting two-sector ATPase complex, catalytic domain.

Source: NCBI Gene 90423 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 48 total
• MANE Select transcript: NM_001318063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18125
Approved symbol	ATP6V1E2
Name	ATPase H+ transporting V1 subunit E2
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	MGC9341, VMA4, ATP6E1
Ensembl gene	ENSG00000250565
Ensembl biotype	protein_coding
OMIM	617385
Entrez	90423

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 18 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000306448, ENST00000505245, ENST00000522219, ENST00000522587, ENST00000524188, ENST00000524249, ENST00000890126, ENST00000890127, ENST00000890128, ENST00000890129, ENST00000890130, ENST00000890131, ENST00000890132, ENST00000890133, ENST00000923418, ENST00000923419, ENST00000923420, ENST00000923421, ENST00000965787, ENST00000965788, ENST00000965789, ENST00000965790

RefSeq mRNA: 4 — MANE Select: NM_001318063 NM_001318063, NM_001371281, NM_001371282, NM_001371283

CCDS: CCDS1826

Canonical transcript exons

ENST00000522587 — 5 exons

Exon	Start	End
ENSE00001169252	46511847	46512812
ENSE00002079314	46536611	46536703
ENSE00002093048	46535813	46535927
ENSE00002097559	46541390	46541453
ENSE00002135498	46542217	46542577

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 95.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.3611 / max 62.2497, expressed in 1243 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28188	2.2572	1226
28186	0.0534	3
28187	0.0505	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	95.88	gold quality
right testis	UBERON:0004534	88.25	gold quality
left testis	UBERON:0004533	88.17	gold quality
testis	UBERON:0000473	86.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.95	gold quality
islet of Langerhans	UBERON:0000006	84.08	gold quality
leukocyte	CL:0000738	81.66	gold quality
monocyte	CL:0000576	81.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.96	gold quality
adult organism	UBERON:0007023	80.49	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.33	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.48	gold quality
muscle of leg	UBERON:0001383	79.45	gold quality
granulocyte	CL:0000094	79.42	gold quality
ventricular zone	UBERON:0003053	79.25	gold quality
gastrocnemius	UBERON:0001388	79.20	gold quality
pancreas	UBERON:0001264	77.92	gold quality
right frontal lobe	UBERON:0002810	77.56	gold quality
anterior cingulate cortex	UBERON:0009835	77.51	gold quality
right adrenal gland	UBERON:0001233	77.41	gold quality
spinal cord	UBERON:0002240	77.33	gold quality
right adrenal gland cortex	UBERON:0035827	77.23	gold quality
prefrontal cortex	UBERON:0000451	77.20	gold quality
putamen	UBERON:0001874	77.09	gold quality
amygdala	UBERON:0001876	76.83	gold quality
caudate nucleus	UBERON:0001873	76.81	gold quality
left adrenal gland	UBERON:0001234	76.76	gold quality
nucleus accumbens	UBERON:0001882	76.72	gold quality
left adrenal gland cortex	UBERON:0035825	76.44	gold quality
calcaneal tendon	UBERON:0003701	76.31	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.57

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• Rat vacuolar H(+)ATPase associates with NHE-RF (Na(+)/H(+) exchanger regulatory factor); the E subunit was co-immunoprecipitated from rat kidney cytosol with NHE-RF antibodies. (PMID:10748165)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp6v1e1a	ENSDARG00000014085
danio_rerio	atp6v1e1b	ENSDARG00000030694
mus_musculus	Atp6v1e2	ENSMUSG00000053375
rattus_norvegicus	Atp6v1e2	ENSRNOG00000015566
drosophila_melanogaster	Vha26	FBGN0283535
caenorhabditis_elegans		WBGENE00006917

Paralogs (1): ATP6V1E1 (ENSG00000131100)

Protein

Protein identifiers

V-type proton ATPase subunit E 2 — Q96A05 (reviewed: Q96A05)

Alternative names: Vacuolar proton pump subunit E 2

All UniProt accessions (2): Q96A05, A0A140VKA8

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of the V1 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.

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.

Tissue specificity. Testis specific.

Similarity. Belongs to the V-ATPase E subunit family.

RefSeq proteins (4): NP_001304992, NP_001358210, NP_001358211, NP_001358212 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002842	ATPase_V1_Esu	Family
IPR038495	ATPase_E_C	Homologous_superfamily

Pfam: PF01991

UniProt features (1 total): chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96A05-F1	93.07	0.86

Function

Pathways and Gene Ontology

Reactome pathways

5 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-9639288	Amino acids regulate mTORC1
R-HSA-983712	Ion channel transport

MSigDB gene sets: 85 (showing top): REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MACROAUTOPHAGY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, HP1SITEFACTOR_Q6, WEBER_METHYLATED_LCP_IN_FIBROBLAST_DN, GOMF_PROTON_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, WEBER_METHYLATED_LCP_IN_SPERM_UP, GOBP_TRANSMEMBRANE_TRANSPORT, KEGG_EPITHELIAL_CELL_SIGNALING_IN_HELICOBACTER_PYLORI_INFECTION, CP2_01

GO Biological Process (3): regulation of macroautophagy (GO:0016241), monoatomic ion transport (GO:0006811), proton transmembrane transport (GO:1902600)

GO Molecular Function (2): proton-transporting ATPase activity, rotational mechanism (GO:0046961), protein binding (GO:0005515)

GO Cellular Component (3): acrosomal vesicle (GO:0001669), cytosol (GO:0005829), proton-transporting two-sector ATPase complex, catalytic domain (GO:0033178)

Reactome top-level categories

Rollup of top-5 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of autophagy	1
macroautophagy	1
transport	1
monoatomic cation transmembrane 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
binding	1
secretory granule	1
cytoplasm	1
cellular anatomical structure	1
proton-transporting two-sector ATPase complex	1
membrane protein complex	1

Protein interactions and networks

STRING

938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V1E2	ATP6V1G3	Q96LB4	886
ATP6V1E2	ATP6V1G2	O95670	875
ATP6V1E2	ATP6V1G1	O75348	875
ATP6V1E2	ATP6V1B1	P15313	863
ATP6V1E2	ATP6V1B2	P21281	863
ATP6V1E2	ATP6V1C2	Q8NEY4	851
ATP6V1E2	ATP6V1D	Q9Y5K8	842
ATP6V1E2	ATP6V1C1	P21283	832
ATP6V1E2	ATP6V1H	Q9UI12	832
ATP6V1E2	ATP6V0D1	P12953	824
ATP6V1E2	ATP6V0A2	Q9Y487	810
ATP6V1E2	ATP6V0A1	Q93050	796
ATP6V1E2	ATP6V0A4	Q9HBG4	795
ATP6V1E2	ATP6V1F	Q16864	794
ATP6V1E2	ATP6V0D2	Q8N8Y2	790

IntAct

40 interactions, top by confidence:

A	B	Type	Score
ATP6V1G1	ATP6V1E2	psi-mi:“MI:0915”(physical association)	0.830
ATP6V1E2	ATP6V1G1	psi-mi:“MI:0915”(physical association)	0.830
ATP6V1G2	ATP6V1E2	psi-mi:“MI:0915”(physical association)	0.670
ATP6V1C2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.640
ATP6V1E2	BBLN	psi-mi:“MI:0915”(physical association)	0.560
BBLN	ATP6V1E2	psi-mi:“MI:0915”(physical association)	0.560
RASSF10	ATP6V1E2	psi-mi:“MI:0915”(physical association)	0.560
MESD	ATP6V1E2	psi-mi:“MI:0915”(physical association)	0.560
ATP6V0A1	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
ATP6V0A4	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
ATP6V1B2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
ATP6V1G2	ATP6V1B1	psi-mi:“MI:0914”(association)	0.530
MAPT	NCAN	psi-mi:“MI:0914”(association)	0.350
ATP6V1C2	POTEF	psi-mi:“MI:0914”(association)	0.350
ATP6V1B1	ATP6V1G1	psi-mi:“MI:0914”(association)	0.350
ATP6AP2	A2M	psi-mi:“MI:0914”(association)	0.350
ATP6V0A2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.350
ATP6V1H	ATP6V1B1	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
ATP6V1G1	ATP6V1E2	psi-mi:“MI:0915”(physical association)	0.000
ATP6V1G2	ATP6V1E2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): ATP6V1E2 (Two-hybrid), ATP6V1E2 (Two-hybrid), ATP6V1E2 (Affinity Capture-MS), ATP6V1E2 (Affinity Capture-MS), ATP6V1E2 (Two-hybrid), ATP6V1G1 (Two-hybrid), ATP6V1E2 (Affinity Capture-MS), ATP6V1E2 (Affinity Capture-MS), ATP6V1E2 (Two-hybrid), ATP6V1E2 (Two-hybrid), ATP6V1E2 (Two-hybrid), ATP6V1E2 (Two-hybrid), ATP6V1E2 (Affinity Capture-MS), ATP6V1E2 (Proximity Label-MS), ATP6V1E2 (Affinity Capture-MS)

ESM2 similar proteins: A1CQI3, A3KNK7, B0WAM5, B0WG73, B2RYZ5, B3MQ24, B3NUB6, B4H2S0, B4IK33, B4JLC3, B4L1Z8, B4M6M6, B4NUB3, B4PY93, B5XC71, B5XGH3, P45437, Q08DS5, Q17MZ8, Q1DRC2, Q1HQY6, Q1JQD4, Q29IN4, Q2F5R8, Q32LB7, Q3KPT5, Q3UQ44, Q498D9, Q4H3N8, Q5BDL9, Q5M759, Q5RC82, Q68EW7, Q6DH42, Q6NQ54, Q6NQH4, Q6P255, Q7QIL8, Q803N9, Q8TF65

Diamond homologs: O00780, O13687, O23948, O94072, P0CAN7, P11019, P22203, P31402, P36543, P50518, P54611, Q01278, Q32LB7, Q39258, Q40272, Q41396, Q4R761, Q6PCU2, Q95X44, Q96A05, Q9C9Z8, Q9D593, Q9MB46, Q9SWE7, Q9U1G5, O27039, Q3J9F2, O06501, Q5JDS0, Q9UXU4, A6UT32, C6A5F1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATP6V1E2	“form complex”	V-ATPase	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 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
Insulin receptor recycling	9	244.7×	1e-19
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	5	239.9×	9e-11
Transferrin endocytosis and recycling	9	236.8×	1e-19
ROS and RNS production in phagocytes	9	215.9×	2e-19
Amino acids regulate mTORC1	6	85.9×	3e-10
Ion channel transport	9	61.7×	3e-14

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	7	344.9×	3e-15
vacuolar acidification	7	269.9×	1e-14
regulation of macroautophagy	8	124.5×	3e-14
proton transmembrane transport	7	115.0×	3e-12

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

247 predictions. Top by Δscore:

Variant	Effect	Δscore
2:46512820:A:T	acceptor_gain	1.0000
2:46543185:GCAG:G	donor_gain	1.0000
2:46543187:AGGT:A	donor_loss	1.0000
2:46543189:G:GG	donor_gain	1.0000
2:46543189:GTA:G	donor_loss	1.0000
2:46512819:CAG:C	acceptor_gain	0.9900
2:46543184:CGCAG:C	donor_gain	0.9900
2:46543185:GCAGG:G	donor_gain	0.9900
2:46543186:CAG:C	donor_gain	0.9900
2:46543187:AG:A	donor_gain	0.9900
2:46543188:GG:G	donor_gain	0.9900
2:46543190:T:G	donor_loss	0.9900
2:46512808:CTCAG:C	acceptor_gain	0.9700
2:46512810:CAG:C	acceptor_gain	0.9700
2:46512812:GC:G	acceptor_loss	0.9700
2:46512813:C:CA	acceptor_loss	0.9700
2:46512813:C:CC	acceptor_gain	0.9700
2:46512821:G:GC	acceptor_gain	0.9700
2:46512833:A:C	acceptor_gain	0.9700
2:46512814:T:A	acceptor_loss	0.9600
2:46512818:CCAG:C	acceptor_gain	0.9600
2:46512821:G:C	acceptor_gain	0.9600
2:46512827:A:T	acceptor_gain	0.9600
2:46512826:C:CT	acceptor_gain	0.9500
2:46512815:A:C	acceptor_gain	0.9400
2:46519779:C:CT	donor_gain	0.9300
2:46519780:T:TT	donor_gain	0.9300
2:46512809:TCAG:T	acceptor_gain	0.9200
2:46512810:CAGC:C	acceptor_gain	0.9200
2:46512819:C:CT	acceptor_loss	0.9200

AlphaMissense

1487 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:46512658:G:C	F18L	0.996
2:46512658:G:T	F18L	0.996
2:46512660:A:G	F18L	0.996
2:46512645:C:G	A23P	0.992
2:46512612:C:G	A34P	0.989
2:46512598:A:C	F38L	0.984
2:46512598:A:T	F38L	0.984
2:46512600:A:G	F38L	0.984
2:46512563:C:G	R50P	0.983
2:46512633:C:G	A27P	0.978
2:46512618:C:G	A32P	0.975
2:46512477:C:G	A79P	0.973
2:46512578:A:G	L45P	0.972
2:46512581:C:G	R44P	0.961
2:46512116:C:G	R199P	0.960
2:46512663:C:G	A17P	0.958
2:46512667:C:A	M15I	0.958
2:46512667:C:G	M15I	0.958
2:46512667:C:T	M15I	0.958
2:46512586:T:A	K42N	0.956
2:46512586:T:G	K42N	0.956
2:46512659:A:C	F18C	0.952
2:46512077:C:G	R212P	0.950
2:46512659:A:G	F18S	0.946
2:46512495:A:G	S73P	0.945
2:46512130:A:C	N194K	0.944
2:46512130:A:T	N194K	0.944
2:46512113:A:G	L200P	0.940
2:46512345:C:G	G123R	0.939
2:46512308:C:G	R135P	0.938

dbSNP variants (sampled 300 via entrez): RS1000118632 (2:46511785 C>T), RS1000162926 (2:46532866 C>G), RS1000378538 (2:46531624 A>G), RS1000486971 (2:46537646 G>C), RS1000506497 (2:46525319 G>A), RS1000572358 (2:46526588 T>C), RS1000639419 (2:46533063 A>C,T), RS1000660005 (2:46530437 C>A), RS1000693159 (2:46538739 T>C), RS1000744851 (2:46539034 C>T), RS1000773624 (2:46536550 G>A,C), RS1000837922 (2:46537977 GA>G,GAA), RS1000878723 (2:46522166 T>C), RS1000928138 (2:46541689 G>A), RS1000944557 (2:46518431 G>A,T)

Disease associations

OMIM: gene MIM:617385 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST005025_31	Anti-saccade response	8.000000e-06
GCST005027_2	Anti-saccade error rate in psychotic disorders	2.000000e-07
GCST010002_390	Refractive error	1.000000e-11
GCST010697_51	Cortical surface area (min-P)	4.000000e-12
GCST010698_64	Subcortical volume (min-P)	3.000000e-09
GCST010699_93	Brain morphology (min-P)	1.000000e-12
GCST010700_22	Cortical thickness (MOSTest)	9.000000e-11
GCST010701_108	Cortical surface area (MOSTest)	4.000000e-12
GCST010702_134	Subcortical volume (MOSTest)	2.000000e-14
GCST010703_146	Brain morphology (MOSTest)	5.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006874	antisaccade response measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

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

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects expression, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
ferrous chloride	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Decitabine	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Phenobarbital	affects expression	1
Quercetin	increases expression	1
Rotenone	increases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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