AQP2

Summary

AQP2 (aquaporin 2, HGNC:634) is a protein-coding gene on chromosome 12q13.12, encoding Aquaporin-2 (P41181). Forms a water-specific channel that provides the plasma membranes of renal collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient.

This gene encodes a water channel protein located in the kidney collecting tubule. It belongs to the MIP/aquaporin family, some members of which are clustered together on chromosome 12q13. Mutations in this gene have been linked to autosomal dominant and recessive forms of nephrogenic diabetes insipidus.

Source: NCBI Gene 359 — RefSeq curated summary.

At a glance

• Gene–disease (curated): diabetes insipidus, nephrogenic, autosomal (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 451 total — 23 pathogenic, 32 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• MANE Select transcript: NM_000486

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:634
Approved symbol	AQP2
Name	aquaporin 2
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167580
Ensembl biotype	protein_coding
OMIM	107777
Entrez	359

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 nonsense_mediated_decay

ENST00000199280, ENST00000550862, ENST00000551526

RefSeq mRNA: 1 — MANE Select: NM_000486 NM_000486

CCDS: CCDS8792

Canonical transcript exons

ENST00000199280 — 4 exons

Exon	Start	End
ENSE00001114567	49955399	49958878
ENSE00001217714	49954155	49954319
ENSE00002384715	49950737	49951190
ENSE00003784258	49954630	49954710

Expression profiles

Bgee: expression breadth ubiquitous, 101 present calls, max score 98.64.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.4047 / max 1178.0754, expressed in 25 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125382	2.3581	25
125386	0.0195	6
125385	0.0117	5
125383	0.0102	3
125384	0.0052	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	98.64	gold quality
metanephros cortex	UBERON:0010533	97.86	gold quality
seminal vesicle	UBERON:0000998	97.72	gold quality
adult organism	UBERON:0007023	97.15	gold quality
adult mammalian kidney	UBERON:0000082	96.86	gold quality
kidney	UBERON:0002113	92.34	gold quality
sperm	CL:0000019	89.49	gold quality
nephron tubule	UBERON:0001231	89.01	gold quality
parotid gland	UBERON:0001831	88.83	silver quality
male germ cell	CL:0000015	88.23	gold quality
metanephros	UBERON:0000081	86.43	gold quality
kidney epithelium	UBERON:0004819	86.24	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.23	gold quality
superficial temporal artery	UBERON:0001614	82.65	gold quality
cauda epididymis	UBERON:0004360	80.94	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	79.96	gold quality
buccal mucosa cell	CL:0002336	79.17	silver quality
cortex of kidney	UBERON:0001225	78.87	gold quality
renal glomerulus	UBERON:0000074	78.18	silver quality
nasal cavity epithelium	UBERON:0005384	78.03	gold quality
metanephric glomerulus	UBERON:0004736	77.28	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.59	gold quality
germinal epithelium of ovary	UBERON:0001304	74.13	gold quality
corpus epididymis	UBERON:0004359	74.13	gold quality
adrenal tissue	UBERON:0018303	74.10	gold quality
type B pancreatic cell	CL:0000169	74.05	gold quality
olfactory bulb	UBERON:0002264	74.02	gold quality
biceps brachii	UBERON:0001507	73.49	gold quality
vastus lateralis	UBERON:0001379	72.75	gold quality
cartilage tissue	UBERON:0002418	72.34	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-135	yes	1046.58
E-CURD-119	yes	28.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, ELF4, GATA2, INPP5K, NFAT5, NFATC1, NFKB1, NFKB2, NFKB, NR1H4, REL, RELA, RELB

miRNA regulators (miRDB)

125 targeting AQP2, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4755-5P	99.71	70.34	2716

Literature-anchored findings (GeneRIF, showing 40)

• increase in urinary AQP2 excretion during normal pregnancy without there being a significant increase in plasma AVP (PMID:11509828)
• mutations cause autosomal dominant nephrogenic diabetes insipidus (PMID:11536078)
• Misrouting, instead of a lack of function, is a mechanism for the ’loss of function’ phenotype in nephrogenic diabetes insipidus (PMID:11929850)
• changes in urinary excretion of aquaporin-2 indicates circulatory blood volume depletion, and estimates the AVP-dependent recovery of circulatory blood volume during the therapeutic period in patients with diabetic ketoacidosis (PMID:12021537)
• Two novel aquaporin-2 mutations responsible for congenital nephrogenic diabetes insipidus in Chinese families. (PMID:12050236)
• Most AQP2 missense mutants in recessive NDI are retained in the endoplasmic reticulum (ER), but AQP2-T125M and AQP2-G175R were reported to be nonfunctional channels unimpaired in their routing to the plasma membrane. (PMID:12191971)
• in collecting duct cells, AQP2 trafficking to vasopressin-sensitive vesicles is phosphorylation-independent and phosphorylation of Ser-256 is necessary for expression of AQP2 in the apical membrane (PMID:12194985)
• A mutation screen of AQP2 in 12 individuals with Meniere’s disease did not identify any sequence alterations or mutations within the four coding exons of AQP2 and their intron-exon junctions. (PMID:12208541)
• The excretion of AQP-2 in urine is abnormal both in liver cirrhosis in which we find less suppression of u-AQP2 by an acute water load and in heart failure with a high baseline level and an exaggerated suppression of u-AQP2 by an acute water load. (PMID:12631357)
• Mixed oligomers of wild-type and mutant AQP2s are mistargeted to basolateral membrane due to dominant-negative effect of mutant. Likely explains pathogenesis of autosomal-dominant nephrogenic diabetes insipidus. (PMID:12787389)
• Data suggest the involvement of different protein quality control processes in the processing of aquaporin 2 mutants. (PMID:12819016)
• reduction in the amounts of AQP-2 and AQP-3 expression, especially in lesions with substantial interstitial fibrosis and nephron loss, as compared with a healthy region of normal kidneys. (PMID:14514735)
• glycosylation is essential for exit from the Golgi complex and sorting of AQP2 to the plasma membrane. (PMID:14593099)
• Data report a frame-shift mutation in aquaporin-2 causing dominant nephrogenic diabetes insipidus. (PMID:14662748)
• Where renal water retention is stimulated via arginine vasopressin (AVP), urinary AQP2 measurements provide a reproducible measurement of the renal actions of AVP. (PMID:15012730)
• population of the Mexican town with nephrogenic diabetes insipidus; 30% of the population was heterozygous for the V168M AQP2 mutation and 1% was homozygous for the mutation. (PMID:15100362)
• AQP2 resides in a recycling compartment at the apical side in polarized MDCK-hAQP2 cells, and its retrieval uses the apical endosomal system and the phosphatidylinositol 3-kinase-dependent pathway. (PMID:15155571)
• exaggerated urinary excretion of AQP-2 is dependent on baroreceptor-mediated release of arginine vasopressin in patients with congestive heart failure. (PMID:15458431)
• The distribution and expression levels of AQP2 in normal human tissue. (PMID:15703994)
• crystallization of recombinantly expressed human AQP2 into two-dimensional protein-lipid arrays and their structural characterization by atomic force microscopy and electron crystallography (PMID:15922355)
• increased protein abundance of ENaC subunits as well as the increased apical targeting of AQP2 may contribute to renal sodium and water retention observed during the development of hypertension in spontaneously hypertensive rats (PMID:15956775)
• Differential regulation of AQP2 trafficking in endosomes by microtubules and actin filaments (PMID:16049696)
• This study shows that aldosterone treatment perturbs diabetes insipidus and is associated with AQP2 redistribution in CNT and iCCD (PMID:16159898)
• The sequence at 256-271 is sufficient for apical trafficking in AQP-2. (PMID:16221200)
• hyperosmolality plays an important role in the stability, degradation, expression, and targeting of ng-AQP2 (PMID:16288724)
• data indicate that AQP2 constitutively recycles between the apical membrane and intracellular vesicles in principal cells in situ (PMID:16449354)
• The high level of endometrial AQP2 expression was observed at the mid-secretory phase, the time of embryo implantation, suggesting that AQP2 might play physiological roles in the uterine receptivity. (PMID:16483614)
• After VP stimulation of renal epithelial cells, AQP2 accumulates at the cell surface, while the V2R is actively internalized. This endocytotic block may involve a reduced capacity of phosphorylated AQP2 to interact with the endocytotic machinery. (PMID:16563128)
• AQP2 mutation in NDI families and perinatal mutation testing is of direct clinical value because early diagnosis and treatment can avert the physical and mental retardation associated with repeated episodes of dehydration. (PMID:16580609)
• The disorder nephrogenic diabetes insipidus (NDI) is inherited in an X-linked or autosomal fashion due to mutations in the genes encoding V2R or AQP2, respectively. (PMID:16825342)
• Two novel mutations were identified in each of AVPR2 and AQP2 underlying Congenital Nephrogenic Diabetes Insipidus in Arab families. (PMID:16845277)
• Increase in urine osmolality and creatinine clearance during the diuretic phase, paralleled by an increase in total AQP2 excretion, suggests that AQP2 can contribute to the urinary concentrating ability early in postnatal life. (PMID:16902321)
• Results demonstrate that a mutant monomer of aquaporin 2 gains a dominant-negative effect that reverses the normal polarized sorting of multimers. (PMID:16968783)
• The presence of AQP2 in human endometrium was also confirmed by RT-PCR. CONCLUSION(S): AQP2 is present in the human endometrium. (PMID:16979638)
• Of note, homology modeling revealed that the two mutations involve two highly conserved residues providing important clues about the role of the wt residues in AQP2 stability and function. (PMID:17192724)
• Urinary AQP2 excretion was absent in patients with severely debilitating mutations, a novel total deletion of the A VPR2 gene, and a novel nonsense mutation W296X. (PMID:17550212)
• 70-kDa heat shock proteins as a AQP2 interactors and have shown for hsc70 that this interaction is involved in AQP2 trafficking. (PMID:17636261)
• Our data indicate that no association exists between the -667 AQP-2 A/G polymorphism and susceptibility to chronic kidney disease or its clinical course. (PMID:17763164)
• vasopressin-induced Ca2+ signal including calmodulin, myosin light chain kinase, calmodulin kinase II, and calcineurin have been implicated in the regulation of aquaporin-2 trafficking and/or water permeability–REVIEW (PMID:17957381)
• A homozygous mutation, R85X, was detected in the aquaporin 2 gene (AQP2) of our patient, which has been described only once previously. (PMID:18040725)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Aqp2	ENSMUSG00000023013
rattus_norvegicus	Aqp2	ENSRNOG00000054378
drosophila_melanogaster	Drip	FBGN0015872
drosophila_melanogaster	Eglp1	FBGN0034882
drosophila_melanogaster	Eglp2	FBGN0034883
drosophila_melanogaster	Eglp3	FBGN0034884
drosophila_melanogaster	Eglp4	FBGN0034885
caenorhabditis_elegans		WBGENE00000170

Paralogs (11): AQP6 (ENSG00000086159), AQP8 (ENSG00000103375), AQP9 (ENSG00000103569), MIP (ENSG00000135517), AQP10 (ENSG00000143595), AQP5 (ENSG00000161798), AQP7 (ENSG00000165269), AQP3 (ENSG00000165272), AQP4 (ENSG00000171885), AQP1 (ENSG00000240583), AQP7B (ENSG00000259916)

Protein

Protein identifiers

Aquaporin-2 — P41181 (reviewed: P41181)

Alternative names: ADH water channel, Aquaporin-CD, Collecting duct water channel protein, WCH-CD, Water channel protein for renal collecting duct

All UniProt accessions (3): P41181, F8VPL3, F8W0S2

UniProt curated annotations — full annotation on UniProt →

Function. Forms a water-specific channel that provides the plasma membranes of renal collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient. Plays an essential role in renal water homeostasis. Could also be permeable to glycerol.

Subunit / interactions. Homotetramer. Interacts with micropeptide MIAC; the interaction leads to a reduction of filamentous actin fibers and inhibition of the EREG/EGFR signaling pathway.

Subcellular location. Apical cell membrane. Basolateral cell membrane. Cell membrane. Cytoplasmic vesicle membrane. Golgi apparatus. trans-Golgi network membrane.

Tissue specificity. Expressed in collecting tubules in kidney medulla (at protein level). Detected in kidney.

Post-translational modifications. Ser-256 phosphorylation is necessary and sufficient for expression at the apical membrane. Endocytosis is not phosphorylation-dependent. N-glycosylated.

Disease relevance. Diabetes insipidus, nephrogenic, 2, autosomal (NDI2) [MIM:125800] A disorder caused by the inability of the renal collecting ducts to absorb water in response to arginine vasopressin. Characterized by excessive water drinking (polydipsia), excessive urine excretion (polyuria), persistent hypotonic urine, and hypokalemia. Inheritance can be autosomal dominant or recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Aquaporins contain two tandem repeats each containing three membrane-spanning domains and a pore-forming loop with the signature motif Asn-Pro-Ala (NPA).

Similarity. Belongs to the MIP/aquaporin (TC 1.A.8) family.

RefSeq proteins (1): NP_000477* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000425	MIP	Family
IPR022357	MIP_CS	Conserved_site
IPR023271	Aquaporin-like	Homologous_superfamily
IPR034294	Aquaporin_transptr	Family

Pfam: PF00230

Catalyzed reactions (Rhea), 2 shown:

• H2O(in) = H2O(out) (RHEA:29667)
• glycerol(in) = glycerol(out) (RHEA:29675)

UniProt features (85 total): sequence variant 30, mutagenesis site 16, helix 11, topological domain 9, transmembrane region 6, intramembrane region 2, short sequence motif 2, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1, glycosylation site 1, strand 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8VVX	ELECTRON CRYSTALLOGRAPHY	2.6
4NEF	X-RAY DIFFRACTION	2.75
8GCL	ELECTRON MICROSCOPY	2.89
4OJ2	X-RAY DIFFRACTION	3.05
8OEE	X-RAY DIFFRACTION	3.15
6QF5	X-RAY DIFFRACTION	3.7
8GHJ	X-RAY DIFFRACTION	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41181-F1	91.22	0.76

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 (1): 256

Glycosylation sites (1): 123

Mutagenesis-validated functional residues (16):

Position	Phenotype
78	does not affect interaction with miac; when associated with a-79.
79	does not affect interaction with miac; when associated with a-78.
148	no effect on sorting from the er to the vesicles, redistribution to apical membrane, or endocytosis.
148	retained in the endoplasmic reticulum.
217	abolishes interaction with miac; when associated with a-221.
221	abolishes interaction with miac; when associated with a-217.
229	no effect on sorting from the er to the vesicles, redistribution to apical membrane, or endocytosis.
231	no effect on sorting from the er to the vesicles, redistribution to apical membrane, or endocytosis.
232	reduces interaction with miac.
244	no effect on sorting from the er to the vesicles, redistribution to apical membrane, or endocytosis.
256	retained in vesicles.
256	expressed in the apical membrane.
262	no effect on expression at the apical cell membrane.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-432047	Passive transport by Aquaporins
R-HSA-382551	Transport of small molecules
R-HSA-445717	Aquaporin-mediated transport

MSigDB gene sets: 234 (showing top): RNGTGGGC_UNKNOWN, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_METANEPHROS_DEVELOPMENT, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_RESPONSE_TO_COPPER_ION, CAGGTCC_MIR492, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, AAAYRNCTG_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, GOBP_RESPONSE_TO_METAL_ION, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GCM_PRKCG, GOBP_WATER_TRANSPORT

GO Biological Process (11): renal water homeostasis (GO:0003091), renal water transport (GO:0003097), water transport (GO:0006833), actin filament organization (GO:0007015), glycerol transmembrane transport (GO:0015793), cellular response to water deprivation (GO:0042631), protein homotetramerization (GO:0051289), cellular response to copper ion (GO:0071280), cellular response to mercury ion (GO:0071288), metanephric collecting duct development (GO:0072205), transmembrane transport (GO:0055085)

GO Molecular Function (5): water transmembrane transporter activity (GO:0005372), glycerol transmembrane transporter activity (GO:0015168), water channel activity (GO:0015250), protein binding (GO:0005515), channel activity (GO:0015267)

GO Cellular Component (13): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), transport vesicle membrane (GO:0030658), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), extracellular exosome (GO:0070062), lumenal side of membrane (GO:0098576), cytoplasm (GO:0005737), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aquaporin-mediated transport	2
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
renal system process	2
water transport	2
cellular response to metal ion	2
plasma membrane region	2
multicellular organismal-level water homeostasis	1
renal water homeostasis	1
fluid transport	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
polyol transmembrane transport	1
carbohydrate transmembrane transport	1
response to water deprivation	1
cellular response to stress	1
cellular response to water stimulus	1
protein homooligomerization	1
protein tetramerization	1
response to copper ion	1
response to mercury ion	1
metanephros development	1
collecting duct development	1
transport	1
cellular process	1
transmembrane transporter activity	1
carbohydrate transmembrane transporter activity	1
polyol transmembrane transporter activity	1
glycerol transmembrane transport	1
water transmembrane transporter activity	1
channel activity	1
binding	1
passive transmembrane transporter activity	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
basal plasma membrane	1
apical part of cell	1
transport vesicle	1
cytoplasmic vesicle membrane	1

Protein interactions and networks

STRING

3279 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AQP2	AVPR2	P30518	981
AQP2	AVP	P01185	908
AQP2	SLC12A1	Q13621	886
AQP2	CLCNKA	P51800	779
AQP2	AQP12A	Q8IXF9	750
AQP2	SLC26A4	O43511	749
AQP2	AQP11	Q8NBQ7	746
AQP2	SLC12A3	P55017	733
AQP2	SCTR	P47872	723
AQP2	STUB1	Q9UNE7	711
AQP2	UMOD	P07911	695
AQP2	SCT	P09683	693
AQP2	SLC9A3	P48764	664
AQP2	KCNJ1	P48048	657
AQP2	SLC4A1	P02730	655

IntAct

121 interactions, top by confidence:

A	B	Type	Score
AQP2	CREB3	psi-mi:“MI:0915”(physical association)	0.560
PMP22	AQP2	psi-mi:“MI:0915”(physical association)	0.560
FAM3C	AQP2	psi-mi:“MI:0915”(physical association)	0.560
NRM	AQP2	psi-mi:“MI:0915”(physical association)	0.560
AQP2	MRM1	psi-mi:“MI:0915”(physical association)	0.560
AQP2	TMEM60	psi-mi:“MI:0915”(physical association)	0.560
AQP2	SLC38A7	psi-mi:“MI:0915”(physical association)	0.560
AQP2	PMP22	psi-mi:“MI:0915”(physical association)	0.560
AQP2	FAM3C	psi-mi:“MI:0915”(physical association)	0.560
AQP2	NRM	psi-mi:“MI:0915”(physical association)	0.560
AQP2	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
AQP2	SLC26A6	psi-mi:“MI:0915”(physical association)	0.560
AQP2	PPGB	psi-mi:“MI:0915”(physical association)	0.560
AQP2	TMEM109	psi-mi:“MI:0915”(physical association)	0.560
TUSC5	AQP2	psi-mi:“MI:0915”(physical association)	0.560
AQP2	GPX8	psi-mi:“MI:0915”(physical association)	0.560
AQP2	RTP2	psi-mi:“MI:0915”(physical association)	0.560
AQP2	EFNA5	psi-mi:“MI:0915”(physical association)	0.560
AQP2	ERMP1	psi-mi:“MI:0915”(physical association)	0.560
AQP2	TMEM236	psi-mi:“MI:0915”(physical association)	0.560
AQP2	YIPF6	psi-mi:“MI:0915”(physical association)	0.560
AQP2	PNLIPRP1	psi-mi:“MI:0915”(physical association)	0.560
MUC1	AQP2	psi-mi:“MI:0915”(physical association)	0.560
AQP2	MS4A13	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (71): CREB3 (Two-hybrid), NDFIP2 (Two-hybrid), STX8 (Two-hybrid), IER3 (Two-hybrid), BCAP31 (Two-hybrid), TMEM230 (Two-hybrid), SPCS1 (Two-hybrid), PLP2 (Two-hybrid), UBE2J1 (Two-hybrid), CCDC167 (Two-hybrid), C14orf1 (Two-hybrid), SSR3 (Two-hybrid), COL4A3BP (Two-hybrid), CLDN7 (Two-hybrid), ACTB (Two-hybrid)

ESM2 similar proteins: A0A075B734, A1L272, A2IBY8, A8W649, A9Y006, D4A7H1, E7EXX2, F7B113, O14520, O35454, O54794, O62735, O94956, P34080, P35525, P41181, P47862, P47863, P47864, P51789, P51797, P56402, P56403, P79099, Q06495, Q06496, Q08DE6, Q4R691, Q5PQL3, Q62052, Q866S3, Q8BLV3, Q8BXB6, Q8BZ00, Q8IVB4, Q8K078, Q8MIQ9, Q8R2N1, Q8TCT8, Q921R8

Diamond homologs: A0A075B734, A0A384JPP3, A0A384JSZ0, A9Y006, B0D4E4, B0D4J9, B0D4K0, B0DLE4, B1VB61, F9USY3, F9UTW9, F9UUB3, G5CTF9, G5CTG0, G5CTG1, G5CTG4, G5CTG5, G5CTG6, G5CTG7, I1CR68, I1CS06, I1RHJ1, I1RIY3, I1Z8E7, I1Z8E8, I1Z8E9, I1Z8F0, I3W9F7, O14520, O43315, O54794, O62735, O77697, O77714, O77722, O77740, P0A3Q7, P0A3Q8, P0AER0, P0AER1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CDK18	“down-regulates quantity by destabilization”	AQP2	phosphorylation
CyclinA2/CDK18	“down-regulates quantity by destabilization”	AQP2	phosphorylation
PKA	“up-regulates activity”	AQP2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	32
Uncertain significance	154
Likely benign	170
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1452845	NM_000486.6(AQP2):c.501_502inv (p.Val168Met)	Pathogenic
1455013	NC_000012.11:g.(?50348473)(50357918_?)del	Pathogenic
1455736	NM_000486.6(AQP2):c.253C>T (p.Arg85Ter)	Pathogenic
1526141	NM_000486.6(AQP2):c.127_128del (p.Gln43fs)	Pathogenic
17831	NM_000486.6(AQP2):c.369del (p.Asn123fs)	Pathogenic
17834	NM_000486.6(AQP2):c.203A>G (p.Asn68Ser)	Pathogenic
17839	NM_000486.6(AQP2):c.543C>G (p.Cys181Trp)	Pathogenic
17843	NM_000486.6(AQP2):c.299G>T (p.Gly100Val)	Pathogenic
1998571	NM_000486.6(AQP2):c.102_104del (p.Trp34_Pro35delinsTer)	Pathogenic
2045823	NM_000486.6(AQP2):c.398_399del (p.Val133fs)	Pathogenic
2113020	NM_000486.6(AQP2):c.261_283del (p.Phe88fs)	Pathogenic
2124687	NM_000486.6(AQP2):c.240del (p.His80fs)	Pathogenic
2137365	NM_000486.6(AQP2):c.606+1G>A	Pathogenic
2700622	NM_000486.6(AQP2):c.500dup (p.Val168fs)	Pathogenic
2811242	NM_000486.6(AQP2):c.782C>A (p.Ser261Ter)	Pathogenic
2842841	NM_000486.6(AQP2):c.692C>A (p.Ser231Ter)	Pathogenic
3244351	NC_000012.11:g.(?50344614)(50349391_?)del	Pathogenic
3244352	NC_000012.11:g.(?50349162)(50349391_?)del	Pathogenic
847319	NM_000486.6(AQP2):c.153dup (p.Ile52fs)	Pathogenic
848236	NM_000486.6(AQP2):c.460G>T (p.Gly154Ter)	Pathogenic
974414	NM_000486.6(AQP2):c.797_*17del (p.Pro266fs)	Pathogenic
988214	NM_000486.6(AQP2):c.375del (p.Thr126fs)	Pathogenic
998050	NM_000486.6(AQP2):c.3G>T (p.Met1Ile)	Pathogenic
1067528	NC_000012.11:g.(?50347928)(50349401_?)del	Likely pathogenic
1481897	NM_000486.6(AQP2):c.559C>G (p.Arg187Gly)	Likely pathogenic
1516570	NM_000486.6(AQP2):c.360+1G>A	Likely pathogenic
17829	NM_000486.6(AQP2):c.646T>C (p.Ser216Pro)	Likely pathogenic
17835	NM_000486.6(AQP2):c.523G>A (p.Gly175Arg)	Likely pathogenic
17836	NM_000486.6(AQP2):c.772G>A (p.Glu258Lys)	Likely pathogenic
17840	NM_000486.6(AQP2):c.721del (p.Glu241fs)	Likely pathogenic

SpliceAI

653 predictions. Top by Δscore:

Variant	Effect	Δscore
12:49951186:ATGCT:A	donor_gain	1.0000
12:49951187:TGCT:T	donor_gain	1.0000
12:49951188:GCT:G	donor_gain	1.0000
12:49951188:GCTG:G	donor_gain	1.0000
12:49951189:CT:C	donor_gain	1.0000
12:49951191:G:GG	donor_gain	1.0000
12:49951192:T:TG	donor_loss	0.9900
12:49951193:GAG:G	donor_loss	0.9900
12:49954150:CCCA:C	acceptor_loss	0.9900
12:49954152:CA:C	acceptor_loss	0.9900
12:49954153:A:AG	acceptor_gain	0.9900
12:49954153:AGC:A	acceptor_loss	0.9900
12:49954154:G:A	acceptor_loss	0.9900
12:49954154:G:GA	acceptor_gain	0.9900
12:49954154:GCTC:G	acceptor_gain	0.9900
12:49954154:GCTCA:G	acceptor_gain	0.9900
12:49954256:A:T	donor_gain	0.9900
12:49954316:TGGGG:T	donor_loss	0.9900
12:49954320:GTA:G	donor_loss	0.9900
12:49954321:T:G	donor_loss	0.9900
12:49951194:A:AG	donor_gain	0.9800
12:49951195:G:GG	donor_gain	0.9800
12:49954154:GC:G	acceptor_gain	0.9800
12:49954243:A:G	donor_gain	0.9800
12:49954317:GGG:G	donor_gain	0.9800
12:49954318:GG:G	donor_gain	0.9800
12:49954318:GGG:G	donor_gain	0.9800
12:49954319:GG:G	donor_gain	0.9800
12:49955393:CCCCA:C	acceptor_loss	0.9800
12:49955394:CCCAG:C	acceptor_loss	0.9800

AlphaMissense

1717 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:49954656:T:A	N184K	0.999
12:49954656:T:G	N184K	0.999
12:49950972:T:C	F48L	0.998
12:49950974:T:A	F48L	0.998
12:49950974:T:G	F48L	0.998
12:49951034:C:A	N68K	0.998
12:49951034:C:G	N68K	0.998
12:49954647:C:G	C181W	0.997
12:49955402:T:C	F204L	0.997
12:49955404:C:A	F204L	0.997
12:49955404:C:G	F204L	0.997
12:49954288:G:A	G165D	0.996
12:49954305:G:C	G171R	0.996
12:49954312:T:C	L173P	0.996
12:49954640:C:T	T179I	0.996
12:49954646:G:A	C181Y	0.996
12:49951045:C:T	T72I	0.995
12:49951129:G:A	G100E	0.995
12:49954318:G:A	G175E	0.995
12:49954654:A:G	N184D	0.995
12:49955405:T:A	W205R	0.995
12:49955405:T:C	W205R	0.995
12:49951032:A:G	N68D	0.994
12:49951116:G:T	G96W	0.994
12:49951117:G:A	G96E	0.994
12:49954194:G:A	E134K	0.994
12:49954195:A:T	E134V	0.994
12:49954216:T:C	L141P	0.994
12:49954317:G:A	G175R	0.994
12:49954317:G:C	G175R	0.994

dbSNP variants (sampled 300 via entrez): RS1000014718 (12:49954493 C>A,G), RS1000083035 (12:49953234 C>G,T), RS1000323629 (12:49954805 G>A,C,T), RS1000926247 (12:49958914 T>C), RS1001046761 (12:49952687 C>G,T), RS1001440376 (12:49952866 C>G), RS1001604847 (12:49956009 T>C,G), RS1001822541 (12:49951514 C>T), RS1002096443 (12:49955782 G>A,C,T), RS1002274585 (12:49952595 A>C,T), RS1002333065 (12:49958006 G>A,T), RS1002336674 (12:49957673 C>T), RS1002437681 (12:49951748 A>T), RS1002508098 (12:49950053 A>C), RS1003045478 (12:49955114 A>C,G)

Disease associations

OMIM: gene MIM:107777 | disease phenotypes: MIM:125800

GenCC curated gene-disease

Disease	Classification	Inheritance
diabetes insipidus, nephrogenic, autosomal	Strong	Autosomal dominant
nephrogenic diabetes insipidus	Supportive	Autosomal dominant

Mondo (4): diabetes insipidus, nephrogenic, autosomal (MONDO:0007451), nephrogenic diabetes insipidus (MONDO:0016383), diabetes insipidus (MONDO:0004782), hereditary disease (MONDO:0003847)

Orphanet (1): Arginine vasopressin resistance (Orphanet:223)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000009	Functional abnormality of the bladder
HP:0000021	Megacystis
HP:0000072	Hydroureter
HP:0000083	Renal insufficiency
HP:0000103	Polyuria
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001561	Polyhydramnios
HP:0001945	Fever
HP:0001955	Unexplained fevers
HP:0001959	Polydipsia
HP:0001986	Hypertonic dehydration
HP:0002013	Vomiting
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002039	Anorexia
HP:0003158	Hyposthenuria
HP:0003228	Hypernatremia
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0004906	Hypernatremic dehydration
HP:0008872	Feeding difficulties in infancy
HP:0009806	Nephrogenic diabetes insipidus
HP:0010677	Enuresis nocturna

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001636_1	Obsessive-compulsive disorder	5.000000e-07
GCST005038_76	Allergic disease (asthma, hay fever or eczema)	1.000000e-11
GCST006409_17	Allergic rhinitis	5.000000e-10

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003919	Diabetes Insipidus	C12.050.351.968.419.135; C12.200.777.419.135; C12.950.419.135; C19.700.159
D018500	Diabetes Insipidus, Nephrogenic	C12.050.351.968.419.135.500; C12.200.777.419.135.500; C12.950.419.135.500
D030342	Genetic Diseases, Inborn	C16.320

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523224 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs296766	Toxicity	3	thiazolidinediones	Diabetes Mellitus;Type 2

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs296766	AQP2	3	3.25	1	thiazolidinediones
rs461872	AQP2		0.00	0
rs3759125	AQP2		0.00	0
rs3759126	AQP2		0.00	0
rs7305534	AQP2		0.00	0
rs7314734	AQP2		0.00	0
rs10875989	AQP2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — Aquaporins

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Chloroquine	affects localization, decreases reaction, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Progesterone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

5 unique, capped per target: 4 admet, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4329560	ADMET	Induction of membrane translocation of biotinylated human AQP2 expressed in rat IMCD cells at 10 to 50 uM after 30 mins by Western blot analysis	Design and synthesis of rosiglitazone-ferulic acid-nitric oxide donor trihybrids for improving glucose tolerance. — Eur J Med Chem
CHEMBL4422157	Binding	Inhibition of AQP2 (unknown origin) expressed in CHO cells assessed as reduction in aquaporin-mediated cell Volume change at 10 uM by light scattering based assay	Novel prodrug salts

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1VC	Abcam A-549 AQP2 KO	Cancer cell line	Male
CVCL_D1ZZ	Abcam HCT 116 AQP2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01245374	PHASE4	COMPLETED	Norditropin NordiFlex® Device Compared to the Device Previously Used by Patients or Parents
NCT01518062	PHASE4	COMPLETED	Safety of Somatropin and Induction of Puberty With 17-beta-oestradiol in Girls With Turner Syndrome
NCT01734486	PHASE4	COMPLETED	Growth Response in Girls With Turner Syndrome
NCT02642653	PHASE4	COMPLETED	Combining Lovastatin and a Parent-Implemented Language Intervention for Fragile X Syndrome
NCT00262301	PHASE3	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT01518036	PHASE3	COMPLETED	Use of Somatropin in Turner Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01563926	PHASE3	COMPLETED	Evaluating Acceptance of New Liquid Somatropin Formulation in Children With Growth Hormone Deficiency
NCT01710696	PHASE3	COMPLETED	Induction of Puberty With 17-beta Estradiol in Girls With Turner Syndrome
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT04042402	PHASE3	ACTIVE_NOT_RECRUITING	Long Term Extension Study in Patients With Primary Hyperoxaluria
NCT05238519	PHASE3	ACTIVE_NOT_RECRUITING	Improved Diagnosis of Familial Hypercholesterolemia Across the Northland (ID-FH)
NCT07587242	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study to Evaluate the Safety and Efficacy of AOC 1044 (Also Referred to as Delpacibart Zotadirsen) in Participants With DMD With Gene Mutations Amenable to Exon 44 Skipping
NCT05190744	PHASE2	COMPLETED	Probenecid (PB) to Treat Hereditary Nephrogenic Diabetes Insipidus (NDI), ADPKD Treated With Tolvaptan, and Severely Polyuric Patients With Previous Lithium Administration
NCT06368817	PHASE2	RECRUITING	A Study of Lower Radiotherapy Dose to Treat Children With CNS Germinoma
NCT06676774	PHASE2	RECRUITING	Effect of Intranasal Oxytocin on Emotion Recognition and Acute Psycho-Social Stress-induced Cortisol Increase in Patients With Central Diabetes Insipidus and Healthy Controls
NCT00261053	PHASE2	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT00358657	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant and Cyclophosphamide, Mycophenolate Mofetil, Tacrolimus, and Sirolimus in Treating Patients With Primary Immunodeficiency Disorders or Noncancerous Inherited Disorders
NCT00578435	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplantation for the Treatment of Genetic Disorders of Erythropoiesis
NCT00851409	PHASE2	COMPLETED	A Study of the Safety and Immunogenicity of Repeated rhC1INH Administration
NCT01135537	PHASE2	TERMINATED	Pharmacokinetics of Thymoglobulin in Paediatric Haematopoietic Stem-cell Transplants
NCT01343953	PHASE2	COMPLETED	Cord Blood Transplantation in Severe Aplastic Anemia
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT02512679	PHASE2	TERMINATED	Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
NCT03301038	PHASE2	RECRUITING	Rifampin in CYP24A1-related Hypercalcemia and Hypercalciuria
NCT03683277	PHASE2	TERMINATED	IPD in RRMM Characterized With Genomic Abnormalities of Adverse Prognostic
NCT03847909	PHASE2	COMPLETED	A Study to Evaluate DCR-PHXC in Children and Adults With Primary Hyperoxaluria Type 1 and Primary Hyperoxaluria Type 2
NCT04069260	PHASE2	TERMINATED	A Phase 2 Study of ELX-02 in Patients With Nephropathic Cystinosis
NCT06490627	PHASE2	RECRUITING	Unraveling the Impact of Thalidomide at Diverse Doses in Transfusion Dependent Beta Thalassemia
NCT02460354	PHASE1	TERMINATED	Metformin and Congenital Nephrogenic Diabetes Insipidus
NCT01401244	PHASE1	COMPLETED	Bioequivalence of Two Somatropin Products (Norditropin® Versus Genotropin®) in Healthy Adult Volunteers
NCT02807961	PHASE1	TERMINATED	Safety, Tolerability, Pharmacokinetics of ELX-02 in Healthy Adult Volunteers
NCT03292302	PHASE1	COMPLETED	Phase 1 Study of ELX-02 in Healthy Adults
NCT03309605	PHASE1	COMPLETED	Phase 1 Study of ELX-02 in Healthy Adult Subjects
NCT00478335	Not specified	COMPLETED	Pharmacologic Treatment of Congenital Nephrogenic Diabetes Insipidus
NCT04939753	Not specified	COMPLETED	Nephrogenic Diabetes Insipidus During Prolonged Sevoflurane Sedation in the ICU: a Retrospective Analysis
NCT05307042	Not specified	UNKNOWN	Decline in Renal Concentration Ability in Lithium Treated Patients
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening