AQP8

Summary

AQP8 (aquaporin 8, HGNC:642) is a protein-coding gene on chromosome 16p12.1, encoding Aquaporin-8 (O94778). Channel that allows the facilitated permeation of water and uncharged molecules, such as hydrogen peroxide and the neutral form of ammonia (NH3), through cellular membranes such as plasma membrane, inner mitochondrial membrane and endoplasmic reticulum membrane of several tissue….

Aquaporin 8 (AQP8) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 8 mRNA is found in pancreas and colon but not other tissues.

Source: NCBI Gene 343 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 51 total — 1 pathogenic
• MANE Select transcript: NM_001169

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:642
Approved symbol	AQP8
Name	aquaporin 8
Location	16p12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000103375
Ensembl biotype	protein_coding
OMIM	603750
Entrez	343

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000219660, ENST00000566125, ENST00000891013, ENST00000891014, ENST00000941548

RefSeq mRNA: 1 — MANE Select: NM_001169 NM_001169

CCDS: CCDS10626

Canonical transcript exons

ENST00000219660 — 6 exons

Exon	Start	End
ENSE00000679825	25221457	25221583
ENSE00000679828	25224362	25224576
ENSE00000829501	25227068	25227202
ENSE00001211568	25216947	25217057
ENSE00002595379	25228444	25228932
ENSE00003538052	25217198	25217445

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 99.86.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3197 / max 283.1324, expressed in 7 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153269	0.1464	5
153272	0.0690	3
153270	0.0432	4
153274	0.0214	4
207815	0.0142	2
153273	0.0129	1
153271	0.0127	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.86	gold quality
body of pancreas	UBERON:0001150	99.15	gold quality
ileal mucosa	UBERON:0000331	96.89	gold quality
rectum	UBERON:0001052	96.76	gold quality
colonic mucosa	UBERON:0000317	93.97	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.00	gold quality
transverse colon	UBERON:0001157	86.72	gold quality
pancreas	UBERON:0001264	85.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.54	gold quality
large intestine	UBERON:0000059	74.36	gold quality
epithelial cell of pancreas	CL:0000083	73.86	silver quality
colon	UBERON:0001155	73.79	gold quality
pancreatic ductal cell	CL:0002079	72.04	silver quality
endometrium epithelium	UBERON:0004811	66.45	gold quality
intestine	UBERON:0000160	65.90	gold quality
tibialis anterior	UBERON:0001385	62.53	silver quality
colonic epithelium	UBERON:0000397	61.90	gold quality
sigmoid colon	UBERON:0001159	61.16	gold quality
buccal mucosa cell	CL:0002336	60.85	gold quality
islet of Langerhans	UBERON:0000006	60.29	gold quality
cerebellar hemisphere	UBERON:0002245	59.46	gold quality
cerebellar cortex	UBERON:0002129	59.44	gold quality
cerebellum	UBERON:0002037	58.27	gold quality
endothelial cell	CL:0000115	57.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	57.56	gold quality
oocyte	CL:0000023	57.34	gold quality
nucleus accumbens	UBERON:0001882	57.00	gold quality
periodontal ligament	UBERON:0008266	56.90	gold quality
vermiform appendix	UBERON:0001154	55.52	gold quality
cerebellar vermis	UBERON:0004720	55.27	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	28.08
E-GEOD-125970	yes	22.98
E-GEOD-81547	yes	19.76
E-CURD-53	no	27.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting AQP8, 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-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378C	98.43	66.10	548
HSA-MIR-378D	98.43	66.10	548
HSA-MIR-378E	98.43	65.99	551
HSA-MIR-378F	98.43	65.66	554
HSA-MIR-378H	98.43	66.16	545
HSA-MIR-378I	98.43	66.10	548
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-3200-5P	97.34	65.97	826

Literature-anchored findings (GeneRIF, showing 40)

• Aquaporin 8 is expressed in colonic epithelial cells but was not detected in colorectal tumors. (PMID:11231887)
• expression of aquaporin 8 water channel in and up-regulation by second messenger cyclic adenosine monophosphate. Aquaporin 8 messenger RNA has relatively short biologic half-life in vitro. (PMID:12712100)
• Upregulation of AQP8 in the colon of ulcerative colitis patients represents a secondary phenomenon which may disturb the physiologic colonic mucus barrier and thus lead to chronic inflammation and ulceration. (PMID:17461471)
• Data show that AQP-1, 3, 8, 9 mRNA expression was detected in both amnion and chorion and can be associated with intramembranous transport and volume regulation of amniotic fluid. (PMID:17545093)
• The expression of AQP8 protein is positively correlated with bcl-2 protein in human cervical carcinoma. (PMID:18788571)
• Knockdown of hepatocyte aquaporin-8 by RNA interference induces defective bile canalicular water transport. (PMID:18948439)
• With the increase of cAMP, AQP8 mRNA and protein expressions significantly increased in WISH cells in vitro. (PMID:19087520)
• The expression of AQP8 mRNA and protein is significantly increased in the amnion and placenta of polyhydramnios, suggesting that AQP8 may play an important role in the regulation of amniotic fluid volume. (PMID:19563057)
• Aquaporin 8 has a role in intramembranous water transport and the balance of amniotic fluid. (PMID:20144166)
• When polyhydramnios occurs, expression of aquaporin 8 and aquaporin 9 in fetal membranes and placenta is an adaptive change. (PMID:20732771)
• Reconstitution of water channel function and 2D-crystallization of human aquaporin 8. (PMID:22192778)
• AQP8 expression significantly increased in advanced stage of cervical cancer, deeper infiltration, metastatic lymph nodes and larger tumor volume. (PMID:22901156)
• AQP8 and its relationship with miRNAs may be involved in the pathogenesis of Ulcerative colitis (UC). (PMID:23595390)
• High Aquaporin 8 expression is associated with invasion of cervical cancer. (PMID:23679281)
• AQP8 has a role in the pathogenesis of PCOS. (PMID:23953589)
• The expression levels and immunoreactive score of AQP8 protein and mRNA increased in low-grade astrocytomas, and further increased in high-grade astrocytomas, especially in glioblastoma. (PMID:24055034)
• mtAQP8 knockdown induces necrotic cell death in human neoplastic hepatic cells, a finding that might be relevant to therapeutic strategies against hepatoma cells. (PMID:24415197)
• the results here reported indicate that AQP8 is able to modulate H2O2 transport through the plasma membrane affecting redox signalling linked to leukaemia cell proliferation (PMID:24440277)
• increased AQP8, Erk1/2 and phosphorylated-Erk1/2 expression may play a role in transformation of cervical intraepithelila neoplasia into cervical cancer, and in early invasion and lymphatic metastasis of cervical cancer (PMID:25120769)
• EGF induces AQP8 expression and cell migration in Eca-109 cells via the EGFR/Erk1/2 signal transduction pathway. (PMID:25550802)
• No significant relationship was found between gallbladder mucosa aquaporin expression and the presence or absence of gallbladder stones. (PMID:26707370)
• AQP6 and AQP8 had different expression degrees in epithelial ovarian tissues, which suggests that AQP6 and AQP8 may play certain roles in epithelial ovarian tumors. (PMID:26779650)
• The control of AQP8-mediated H2O2 transport provides a novel mechanism to regulate cell signaling and survival during stress. (PMID:26972385)
• In particular, AQP8 affected VEGF-induced redox signaling by increasing the sulfenation of the tumor suppressor PTEN, which resulted in its inactivation and, in turn, caused Akt activation. (PMID:27862460)
• Aquaporins AQP3, -7, -8, and -11 proteins were found in sperm cells and localized in the head (AQP7), in the middle piece (AQP8) and in the tail (AQP3 and -11) in both the plasma membrane and in intracellular structures. (PMID:28042826)
• Aquaporin 8 expression is regulated by cholesterol in hepatic cells (PMID:28322010)
• Structural basis for mutations in human AQP8 associated with colorectal cancer has been described. (PMID:29799470)
• Mitochondrial AQP8 is involved in SREBP2-controlled hepatocyte cholesterol biosynthesis. (PMID:30579780)
• The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis. (PMID:32016376)
• Aquaporin 8 is involved in H2 O2 -mediated differential regulation of metabolic signaling by alpha1 - and beta-adrenoceptors in hepatocytes. (PMID:32115689)
• HPV Infection Affects Human Sperm Functionality by Inhibition of Aquaporin-8. (PMID:32429588)
• Identification of the AQP8-miR-92a network associated with the aggressive traits of colorectal cancer. (PMID:32446370)
• Role of ROCK/NFkappaB/AQP8 signaling in ethanolinduced intestinal epithelial barrier dysfunction. (PMID:32705263)
• Differential expression and inhibitory effects of aquaporins on the development of adenomyosis. (PMID:32901888)
• Osmotic regulation of aquaporin-8 expression in retinal pigment epithelial cells in vitro: Dependence on KATP channel activation. (PMID:33456300)
• Further evidence for the involvement of mitochondrial aquaporin-8 in hepatocyte lipid synthesis. (PMID:33493534)
• Decreased Tumoral Expression of Colon-Specific Water Channel Aquaporin 8 Is Associated With Reduced Overall Survival in Colon Adenocarcinoma. (PMID:33990498)
• Aquaporin-8 is a novel marker for progression of human cervical cancer cells. (PMID:34151838)
• Osmotic pressure induces translocation of aquaporin-8 by P38 and JNK MAPK signaling pathways in patients with functional constipation. (PMID:36792433)
• AQP8 may affect glioma proliferation and growth by regulating GSK-3beta phosphorylation and nuclear transport of beta-catenin. (PMID:37081713)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	aqp8a.1	ENSDARG00000045141
mus_musculus	Aqp8	ENSMUSG00000030762
rattus_norvegicus	Aqp8	ENSRNOG00000014652
drosophila_melanogaster	Eglp1	FBGN0034882
drosophila_melanogaster	Eglp2	FBGN0034883
drosophila_melanogaster	Eglp3	FBGN0034884
drosophila_melanogaster	Eglp4	FBGN0034885
caenorhabditis_elegans		WBGENE00000172

Paralogs (11): AQP6 (ENSG00000086159), AQP9 (ENSG00000103569), MIP (ENSG00000135517), AQP10 (ENSG00000143595), AQP5 (ENSG00000161798), AQP7 (ENSG00000165269), AQP3 (ENSG00000165272), AQP2 (ENSG00000167580), AQP4 (ENSG00000171885), AQP1 (ENSG00000240583), AQP7B (ENSG00000259916)

Protein

Protein identifiers

Aquaporin-8 — O94778 (reviewed: O94778)

All UniProt accessions (2): O94778, A0A0C4DGL6

UniProt curated annotations — full annotation on UniProt →

Function. Channel that allows the facilitated permeation of water and uncharged molecules, such as hydrogen peroxide and the neutral form of ammonia (NH3), through cellular membranes such as plasma membrane, inner mitochondrial membrane and endoplasmic reticulum membrane of several tissues. The transport of the ammonia neutral form induces a parallel transport of proton, at alkaline pH when the concentration of ammonia is high. However, it is unclear whether the transport of proton takes place via the aquaporin or via an endogenous pathway. Also, may transport ammonia analogs such as formamide and methylamine, a transport favourited at basic pH due to the increase of unprotonated (neutral) form, which is expected to favor diffusion. Does not transport urea or glycerol. The water transport mechanism is mercury- and copper-sensitive and passive in response to osmotic driving forces. At the canicular plasma membrane, mediates the osmotic transport of water toward the bile canaliculus and facilitates the cAMP-induced bile canalicular water secretion, a process involved in bile formation. In addition, mediates the hydrogen peroxide release from hepatocyte mitochondria that modulates the SREBF2-mediated cholesterol synthesis and facilitates the mitochondrial ammonia uptake which is metabolized into urea, mainly under glucagon stimulation. In B cells, transports the CYBB-generated hydrogen peroxide from the external leaflet of the plasma membrane to the cytosol to promote B cell activation and differentiation for signal amplification. In the small intestine and colon system, mediates water transport through mitochondria and apical membrane of epithelial cells. May play an important role in the adaptive response of proximal tubule cells to acidosis possibly by facilitating the mitochondrial ammonia transport.

Subcellular location. Cell membrane. Mitochondrion inner membrane. Apical cell membrane. Basolateral cell membrane. Smooth endoplasmic reticulum membrane.

Tissue specificity. Detected in the sperm midpiece (at protein level). Expressed only in pancreas and colon.

Post-translational modifications. Sulfenylation at Cys-53(C53-SOH) when hydrogen peroxide flows through the AQP8 channel, making it susceptible to hydrogen sulfide produced by CBS. Persulfidation at Cys-53 is required to gate AQP8 channel; under stress condition, hydrogen peroxide accumulates in the cell leading to CBS activation that produces hydrogen sulfide inducing persulfidation of oxidized Cys-53 (C53-SOH). N-glycosylated.

Activity regulation. Reversibly gated by a two-step sulfenylation-persulfidation process in cells undergoing diverse stresses.

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).

Induction. Regulated by osmotic stress. Up-regulated in response to metabolic acidosis.

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

RefSeq proteins (1): NP_001160* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000425	MIP	Family
IPR022357	MIP_CS	Conserved_site
IPR023271	Aquaporin-like	Homologous_superfamily
IPR023277	Aquaporin_8	Family
IPR034294	Aquaporin_transptr	Family

Pfam: PF00230

Catalyzed reactions (Rhea), 4 shown:

• H2O(in) = H2O(out) (RHEA:29667)
• H2O2(out) = H2O2(in) (RHEA:74375)
• formamide(out) = formamide(in) (RHEA:74387)
• methylamine(out) = methylamine(in) (RHEA:74391)

UniProt features (33 total): mutagenesis site 10, topological domain 7, transmembrane region 6, short sequence motif 2, modified residue 2, glycosylation site 2, sequence variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94778-F1	91.05	0.84

Functional residue map

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

Post-translational modifications (2): 53, 53

Glycosylation sites (2): 59, 139

Mutagenesis-validated functional residues (10):

Position	Phenotype
8	does not affect loss of hydrogen peroxide transport after stress.
38	does not affect loss of hydrogen peroxide transport after stress.
48	loss of hydrogen peroxide transport activity under stress condition.
53	does not affect hydrogen peroxide transport under stress condition.
72	does not affect hydrogen peroxide transport activity under stress condition.
173	loss of hydrogen peroxide transporter activity.
173	slightly affect hydrogen peroxide transport after stress.
208	does not affect loss of hydrogen peroxide transport after stress.
213	does not affect hydrogen peroxide transport activity under stress condition.
247	does not affect loss of hydrogen peroxide transport after stress.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-432047	Passive transport by Aquaporins
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells
R-HSA-1266738	Developmental Biology
R-HSA-2262752	Cellular responses to stress
R-HSA-382551	Transport of small molecules
R-HSA-445717	Aquaporin-mediated transport
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9734767	Developmental Cell Lineages

MSigDB gene sets: 180 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_B_CELL_ACTIVATION, MODULE_64, MODULE_16, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, MODULE_118, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_CHOLESTEROL_BIOSYNTHETIC_PROCESS, GOBP_WATER_TRANSPORT, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, UEDA_PERIFERAL_CLOCK, MODULE_379, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_ONE_CARBON_COMPOUND_TRANSPORT

GO Biological Process (15): water transport (GO:0006833), urea transport (GO:0015840), methylammonium transport (GO:0015843), B cell differentiation (GO:0030183), transepithelial water transport (GO:0035377), regulation of cholesterol biosynthetic process (GO:0045540), cellular response to cAMP (GO:0071320), ammonium transmembrane transport (GO:0072488), hydrogen peroxide transmembrane transport (GO:0080170), ammonium import across plasma membrane (GO:0140157), cellular detoxification (GO:1990748), one-carbon compound transport (GO:0019755), transmembrane transport (GO:0055085), urea transmembrane transport (GO:0071918), methylammonium transmembrane transport (GO:0072489)

GO Molecular Function (6): ammonium channel activity (GO:0008519), water channel activity (GO:0015250), methylammonium channel activity (GO:0015264), urea channel activity (GO:0015265), protein binding (GO:0005515), channel activity (GO:0015267)

GO Cellular Component (14): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), smooth endoplasmic reticulum (GO:0005790), plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), smooth endoplasmic reticulum membrane (GO:0030868), brush border membrane (GO:0031526), mitochondrial membrane (GO:0031966), apical part of cell (GO:0045177), intracellular canaliculus (GO:0046691), intracellular vesicle (GO:0097708), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Cellular response to chemical stress	1
Aquaporin-mediated transport	1
Developmental Cell Lineages of the Exocrine Pancreas	1
Cellular responses to stimuli	1
Transport of small molecules	1
Cellular responses to stress	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transmembrane transport	4
channel activity	4
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
one-carbon compound transport	2
nitrogen compound transport	2
ammonium transmembrane transport	2
cellular process	2
transport	2
cytoplasm	2
plasma membrane region	2
apical plasma membrane	2
fluid transport	1
amine transport	1
lymphocyte differentiation	1
B cell activation	1
water transport	1
epithelial fluid transport	1
cholesterol biosynthetic process	1
regulation of cholesterol metabolic process	1
regulation of sterol biosynthetic process	1
regulation of alcohol biosynthetic process	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
inorganic cation import across plasma membrane	1
cellular response to toxic substance	1
detoxification	1
urea transport	1
methylammonium transport	1
water transmembrane transporter activity	1
methylammonium transmembrane transporter activity	1
urea transmembrane transporter activity	1
binding	1
passive transmembrane transporter activity	1
organelle inner membrane	1
mitochondrial membrane	1
endoplasmic reticulum	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2690 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AQP8	AQP11	Q8NBQ7	910
AQP8	AQP10	Q96PS8	889
AQP8	AQP12A	Q8IXF9	887
AQP8	AQP7	O14520	573
AQP8	LCMT1	Q9UIC8	550
AQP8	MS4A12	Q9NXJ0	544
AQP8	GUCA2A	Q02747	509
AQP8	AQP12B	A6NM10	498
AQP8	SLC26A3	P40879	452
AQP8	CLCA4	Q14CN2	452
AQP8	ZG16	O60844	447
AQP8	AQP3	Q92482	427
AQP8	GUCA2B	Q16661	411
AQP8	ESR2	Q92731	385
AQP8	SLC14A1	Q13336	383

IntAct

46 interactions, top by confidence:

A	B	Type	Score
AQP8	CYBC1	psi-mi:“MI:0915”(physical association)	0.560
AQP8	PLP2	psi-mi:“MI:0915”(physical association)	0.560
AQP8	PLPP6	psi-mi:“MI:0915”(physical association)	0.560
TMEM120B	AQP8	psi-mi:“MI:0915”(physical association)	0.560
AQP8	SERP1	psi-mi:“MI:0915”(physical association)	0.560
AQP8	STX12	psi-mi:“MI:0915”(physical association)	0.560
AQP8		psi-mi:“MI:0915”(physical association)	0.560
AQP8	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
AQP8	PRPS1	psi-mi:“MI:0915”(physical association)	0.560
AQP8	WFS1	psi-mi:“MI:0915”(physical association)	0.560
AQP8	BAG6	psi-mi:“MI:0915”(physical association)	0.560
KLF11	AQP8	psi-mi:“MI:0915”(physical association)	0.560
AQP8	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
AQP8	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
AQP8	RNF11	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (7): AQP8 (Two-hybrid), STX12 (Two-hybrid), SERP1 (Two-hybrid), C17orf62 (Two-hybrid), TMEM120B (Two-hybrid), PPAPDC2 (Two-hybrid), AQP8 (Affinity Capture-MS)

ESM2 similar proteins: A0A125YZH9, A0A804KTT0, C8ZJM1, G5CTF8, G5CTG1, G5CTG3, I3W9F6, O94778, P0CD92, P25794, P56405, P61837, P61838, Q06611, Q08451, Q0IWF3, Q0JPT5, Q1M1A0, Q1M2P4, Q39196, Q41870, Q54V53, Q54WT8, Q5I4F8, Q6ZXT3, Q7EYH7, Q84S07, Q8LAA6, Q8LAI1, Q8LFP7, Q8SRK2, Q8VZW1, Q8W036, Q8W037, Q9AQU5, Q9AR14, Q9ASI1, Q9ATM2, Q9ATM3, Q9ATN0

Diamond homologs: A0A125YZH9, A0A6M3QG69, A2IBY8, A4L9J0, F9UUD2, O64964, O68874, O82316, O94778, P06624, P09011, P25818, P28238, P30301, P50156, P51180, P55064, P56404, P56405, P60844, P60845, Q06019, Q0JPT5, Q13520, Q41963, Q5I4F8, Q651D5, Q6J8I9, Q6RZ07, Q6Z2T3, Q75GA5, Q7N5C1, Q7NNP3, Q7XLR1, Q84RL7, Q8GRI8, Q8X6K6, Q92R43, Q94CS9, Q9AR14

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	41
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
58734	GRCh38/hg38 16p12.2-12.1(chr16:21600992-28323344)x1	Pathogenic

SpliceAI

743 predictions. Top by Δscore:

Variant	Effect	Δscore
16:25221455:A:AG	acceptor_gain	1.0000
16:25221456:G:GG	acceptor_gain	1.0000
16:25224572:GCTGG:G	donor_gain	1.0000
16:25224575:GG:G	donor_gain	1.0000
16:25224576:GG:G	donor_gain	1.0000
16:25224577:G:GG	donor_gain	1.0000
16:25221447:T:TA	acceptor_gain	0.9900
16:25221448:G:A	acceptor_gain	0.9900
16:25221455:A:AT	acceptor_loss	0.9900
16:25221455:AGT:A	acceptor_gain	0.9900
16:25221456:GT:G	acceptor_gain	0.9900
16:25221456:GTG:G	acceptor_gain	0.9900
16:25221456:GTGGT:G	acceptor_gain	0.9900
16:25224574:TGG:T	donor_gain	0.9900
16:25224574:TGGGT:T	donor_loss	0.9900
16:25224575:GGG:G	donor_gain	0.9900
16:25224577:G:GA	donor_loss	0.9900
16:25224578:T:G	donor_loss	0.9900
16:25224579:G:GG	donor_loss	0.9900
16:25224580:AGTGT:A	donor_loss	0.9900
16:25225569:GC:G	donor_gain	0.9900
16:25225570:C:G	donor_gain	0.9900
16:25227066:AG:A	acceptor_gain	0.9900
16:25227066:AGG:A	acceptor_gain	0.9900
16:25227067:GG:G	acceptor_gain	0.9900
16:25227067:GGG:G	acceptor_gain	0.9900
16:25227198:ATTAG:A	donor_loss	0.9900
16:25227199:TTAG:T	donor_loss	0.9900
16:25227200:TAG:T	donor_loss	0.9900
16:25227201:AGGTA:A	donor_loss	0.9900

AlphaMissense

1663 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:25227095:T:A	N210K	0.998
16:25227095:T:G	N210K	0.998
16:25221472:C:A	N92K	0.996
16:25221472:C:G	N92K	0.996
16:25221483:C:T	S96F	0.994
16:25217403:G:A	G73E	0.990
16:25221470:A:G	N92D	0.989
16:25221483:C:A	S96Y	0.989
16:25224546:G:A	G191D	0.989
16:25227102:C:A	R213S	0.989
16:25221566:G:T	G124W	0.988
16:25221567:G:A	G124E	0.988
16:25227112:G:A	G216E	0.988
16:25217315:G:C	G44R	0.987
16:25224456:A:T	E161V	0.987
16:25217316:G:A	G44D	0.986
16:25221462:G:A	G89E	0.986
16:25217414:G:A	G77R	0.985
16:25217414:G:C	G77R	0.985
16:25227093:A:G	N210D	0.985
16:25221557:G:A	G121R	0.984
16:25221557:G:C	G121R	0.984
16:25221566:G:A	G124R	0.984
16:25221566:G:C	G124R	0.984
16:25217402:G:T	G73W	0.983
16:25221555:G:A	G120E	0.983
16:25224456:A:C	E161A	0.983
16:25227087:T:C	C208R	0.983
16:25227103:G:C	R213P	0.983
16:25227156:T:A	W231R	0.983

dbSNP variants (sampled 300 via entrez): RS1000116912 (16:25215236 G>T), RS1000199373 (16:25216356 C>T), RS1000371030 (16:25219385 GA>G), RS1000942487 (16:25221087 C>T), RS1001053118 (16:25226873 C>A,T), RS1001240355 (16:25214958 T>C,G), RS1001313331 (16:25224367 G>A), RS1001484357 (16:25226618 G>A), RS1001532951 (16:25225698 G>A), RS1001699200 (16:25224622 G>A,C,T), RS1002214131 (16:25218902 C>T), RS1002217870 (16:25216038 T>G), RS1002394924 (16:25221876 T>C), RS1002698906 (16:25223202 A>G), RS1002758105 (16:25222721 A>G)

Disease associations

OMIM: gene MIM:603750 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003628_6	Clozapine-induced agranulocytosis/granulocytopenia in treatment-resistant schizophrenia	2.000000e-06

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: other ic — Aquaporins

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
Capecitabine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Carmustine	decreases expression	1
Hydrogen Peroxide	increases transport	1
Mercuric Chloride	decreases activity, decreases reaction, increases transport	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	decreases methylation	1
Water	increases transport, decreases reaction	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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