AQP5

Summary

AQP5 (aquaporin 5, HGNC:638) is a protein-coding gene on chromosome 12q13.12, encoding Aquaporin-5 (P55064). Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient.

Aquaporin 5 (AQP5) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 5 plays a role in the generation of saliva, tears and pulmonary secretions. AQP0, AQP2, AQP5, and AQP6 are closely related and all map to 12q13.

Source: NCBI Gene 362 — RefSeq curated summary.

At a glance

• Gene–disease (curated): palmoplantar keratoderma, Bothnian type (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 85 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes
• MANE Select transcript: NM_001651

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:638
Approved symbol	AQP5
Name	aquaporin 5
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000161798
Ensembl biotype	protein_coding
OMIM	600442
Entrez	362

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000293599, ENST00000553132, ENST00000857226

RefSeq mRNA: 1 — MANE Select: NM_001651 NM_001651

CCDS: CCDS8793

Canonical transcript exons

ENST00000293599 — 4 exons

Exon	Start	End
ENSE00001060405	49963492	49963656
ENSE00001060406	49964092	49964175
ENSE00001162987	49961872	49962380
ENSE00001217152	49964992	49965682

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 99.15.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.3117 / max 1320.0658, expressed in 129 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125393	2.7004	104
125395	0.4807	36
125394	0.0930	9
125396	0.0376	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	99.15	gold quality
palpebral conjunctiva	UBERON:0001812	98.31	gold quality
left testis	UBERON:0004533	98.16	gold quality
right testis	UBERON:0004534	97.94	gold quality
parotid gland	UBERON:0001831	97.73	gold quality
nasal cavity mucosa	UBERON:0001826	94.97	gold quality
testis	UBERON:0000473	94.64	gold quality
skin of leg	UBERON:0001511	93.53	gold quality
saliva-secreting gland	UBERON:0001044	92.32	gold quality
nasal cavity epithelium	UBERON:0005384	92.07	gold quality
minor salivary gland	UBERON:0001830	90.74	gold quality
trachea	UBERON:0003126	88.63	gold quality
zone of skin	UBERON:0000014	88.32	gold quality
skin of abdomen	UBERON:0001416	87.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.73	gold quality
mouth mucosa	UBERON:0003729	84.82	gold quality
lower esophagus mucosa	UBERON:0035834	83.13	gold quality
epithelium of bronchus	UBERON:0002031	82.87	gold quality
bronchus	UBERON:0002185	82.85	gold quality
bronchial epithelial cell	CL:0002328	81.31	gold quality
lens of camera-type eye	UBERON:0000965	79.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.01	gold quality
adult organism	UBERON:0007023	75.49	gold quality
body of stomach	UBERON:0001161	74.74	gold quality
upper arm skin	UBERON:0004263	74.21	silver quality
upper lobe of left lung	UBERON:0008952	73.69	gold quality
esophagus mucosa	UBERON:0002469	73.50	gold quality
upper leg skin	UBERON:0004262	72.24	gold quality
sperm	CL:0000019	72.16	silver quality
stomach	UBERON:0000945	71.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10283	yes	853.15
E-CURD-114	yes	60.61
E-GEOD-134144	yes	31.49
E-HCAD-1	yes	10.91
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ARNT, ELK3, FOS, GATA6, HIF1A, HMGA2, IRF6, JUN, NFKB, NFKBIA, RELA, SP1

miRNA regulators (miRDB)

22 targeting AQP5, 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-5193	100.00	67.26	1744
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-5094	98.63	67.11	1062
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-1226-3P	97.51	66.32	1063
HSA-MIR-4653-5P	97.22	67.72	1429
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-3943	95.87	64.57	523

Literature-anchored findings (GeneRIF, showing 40)

• This is the first reliable investigation of the regulation of MUC5AC mucin secretion by silencing AQP5. (PMID:16500622)
• TRPV4 participates in hypotonic reduction of AQP5. (PMID:16537379)
• hyperosmotic stress is an important activator of AQP-5 in human airway epithelium, leading to significantly increased transepithelial water permeability (PMID:17043812)
• These results show that IL-13 interferes with ion and water channel expression and localization during epithelial regeneration and may thereby influence mucus composition and hydration. (PMID:17553491)
• The decreased expression of AQP5 mRNA may be related to the severity of airflow obstruction. (PMID:17640479)
• We conclude that AQP5 membrane targeting can include more than one mechanism besides cAMP dependent phosphorylation. (PMID:18042467)
• elements found in the aquaporin-5 and the Rad9 (radiation-sensitive 9) genes showed selective AR versus GR binding in band-shift assays and a strong activity and selectivity in functional assays, both as isolated elements and in their original contexts (PMID:18215141)
• The data suggest potential roles of AQP3 and 5 in the regulation of airway hypersecretion, perhaps ultimately providing a target for treating such diseases (PMID:18280225)
• AQP5 expression was needed for shear-induced barrier enhancement (PMID:18305162)
• Genetic background differences or a distinct pathogenetic Keratoconus (KC) cascade specific to the analyzed population could account for the dissimilarities observed in KC-related AQP5 expression. (PMID:18449356)
• AQP5, through its phosphorylation on Ser156 and subsequent interaction with c-Src, plays an important role in NSCLC invasion and, therefore, may provide a unique opportunity for developing a novel therapeutic target as well as a prognostic marker in NSCLC (PMID:18478076)
• There is an induction of hAQP5 expression during colorectal carcinogenesis. hAQP5 ingteracts with the Ras/extracellular signal-regulated kinase/retinoblastoma protein signaling pathway, identifying hAQP5 as a novel therapeutic target. (PMID:18583321)
• AQP5 is overexpressed in chronic myelogenous leukemia cells and plays a role in promoting cell proliferation and inhibiting apoptosis. (PMID:18612408)
• C terminus may arise from the phosphorylation of AQP5 and thereby signal trafficking (PMID:18768791)
• A single nucleotide polymorphism in the AQP5 gene promoter alters AQP5 expression in different in vitro systems and cells, and is associated with alterations of variables of the RAAS both in young healthy males and patients with coronary artery disease. (PMID:18846354)
• The +2254A to G variant in intron 3 of AQP5 was associated with a decreased risk of COPD in a Chinese population. (PMID:18853286)
• AQP5 was expressed more highly in patients with nasal polyps and allergic rhinitis than in patients with nasal polyps alone. (PMID:19166033)
• Up-regulation of AQP5 may be involved in differentiation of human gastric cancer cells. (PMID:19340551)
• expressed in primary human lung parenchyma mesenchymal stromal cells (PMID:19652646)
• When inhibiting the proliferation of ovarian cancer cells, topotecan may down-regulate the expression of AQP5 and NF-kappaB. (PMID:19664333)
• AQP3, 4 & 5 exhibited differential expression between human gastric carcinoma & corresponding normal tissue;AQP3 & AQP5 expression were associated with lymph node metastasis & lymphovascular invasion (PMID:20106632)
• AQP5 transcription and protein expression were down-regulated after exposure to lipopolysaccharide via the p38/JNK signaling pathway. (PMID:20362698)
• AQP5, HIF-1alpha, VEGF are all involved in edema formation in nasal polyps. (PMID:20669661)
• The purpose of this study was to determine the effects of down-regulation of Aquaporin 1 (AQP1) and Aquaporin 5 (AQP5) on cell proliferation and migration in human corneal endothelial (HCEC) and human corneal epithelial (CEPI17) cell lines, respectively. (PMID:20806077)
• Aquaporin 5 polymorphisms have a role in rate of lung function decline in chronic obstructive pulmonary disease (PMID:21151978)
• AQP1 and AQP5 might play an important role in the development of lung edema and lung injury (PMID:21244858)
• Treatment of A549 cells with tanshinone IIA can decrease the overexpression of AQP5 induced by seawater. (PMID:21251364)
• Aquaporin-5, which mediates water permeability and thus regulates cell shape and volume, is a potentially important determinant in cell migration. (PMID:21315850)
• Aquaporin 5 gene promoter–1364A/C polymorphism associated with 30-day survival in severe sepsis. (PMID:21427539)
• AQP5 expression increases MUC5AC and MUC5B mucin production (PMID:21455588)
• AQP5-IR was found on apical and basolateral membranes of acinar cells, and showed a “mosaic” pattern, i.e., with some acini and/or acinar cells showing stronger AQP5-IR than others. (PMID:21524183)
• Numbers of AQP-5-positive coils in the secretory part of eccrine sweat glands were decreased in Sjogren’s syndrome, but not in skin affected by idiopathic segmental anhidrosis or idiopathic pure sudomotor failure. (PMID:21950762)
• TNF-alpha inhibition of AQP5 expression in human salivary gland acinar cells is due to the epigenetic mechanism by suppression of acetylation of histone H4. (PMID:21973049)
• These observations suggest that AQP5 plays a key role in cervical cancer (PMID:22048942)
• AQP5 overexpression is associated with cell growth and metastasis of human breast cancer. (PMID:22145049)
• the results of this study suggest that AQP-5 expression may be associated with prognosis and drug sensitivity in biliary tract carcinoma (PMID:22470085)
• expression of aquaporin 1 and 5 was higher in uterine leiomyomata than in unaffected uteri (PMID:22472942)
• Overexpression of both AQP5 and AQP3 were immunohistochemically observed on tumor cells in squamous cell carcinoma (PMID:22576684)
• These findings indicate that AQP5-mediated regulation of microtubule dynamics modulates airway epithelial barrier properties and epithelial function. (PMID:22715407)
• The potential functions of AQP2 and AQP5 are in the resorption and secretion of endolymph. (Review) (PMID:22732097)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	aqp10a	ENSDARG00000007086
danio_rerio	aqp10b	ENSDARG00000058678
danio_rerio	aqp8a.2	ENSDARG00000071592
danio_rerio	aqp8b	ENSDARG00000089749
mus_musculus	Aqp5	ENSMUSG00000044217
rattus_norvegicus	Aqp5	ENSRNOG00000051970
drosophila_melanogaster	Drip	FBGN0015872
drosophila_melanogaster	Eglp1	FBGN0034882
drosophila_melanogaster	Eglp2	FBGN0034883
drosophila_melanogaster	Eglp3	FBGN0034884
drosophila_melanogaster	Eglp4	FBGN0034885

Paralogs (11): AQP6 (ENSG00000086159), AQP8 (ENSG00000103375), AQP9 (ENSG00000103569), MIP (ENSG00000135517), AQP10 (ENSG00000143595), AQP7 (ENSG00000165269), AQP3 (ENSG00000165272), AQP2 (ENSG00000167580), AQP4 (ENSG00000171885), AQP1 (ENSG00000240583), AQP7B (ENSG00000259916)

Protein

Protein identifiers

Aquaporin-5 — P55064 (reviewed: P55064)

All UniProt accessions (1): P55064

UniProt curated annotations — full annotation on UniProt →

Function. Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient. Plays an important role in fluid secretion in salivary glands. Required for TRPV4 activation by hypotonicity. Together with TRPV4, controls regulatory volume decrease in salivary epithelial cells. Seems to play a redundant role in water transport in the eye, lung and in sweat glands.

Subunit / interactions. Homotetramer; each monomer provides an independent water pore. Interacts with TRPV4; the interaction is probably indirect and regulates TRPV4 activation by hypotonicity.

Subcellular location. Apical cell membrane. Cell membrane. Cytoplasmic vesicle membrane.

Tissue specificity. Detected in skin eccrine sweat glands, at the apical cell membrane and at intercellular canaliculi (at protein level).

Disease relevance. Keratoderma, palmoplantar, Bothnian type (PPKB) [MIM:600231] A dermatological disorder characterized by diffuse non-epidermolytic hyperkeratosis of the skin of palms and soles. PPKB is frequently complicated by fungal infections. 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_001642* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000425	MIP	Family
IPR022357	MIP_CS	Conserved_site
IPR023271	Aquaporin-like	Homologous_superfamily
IPR023276	Aquaporin_5	Family
IPR034294	Aquaporin_transptr	Family

Pfam: PF00230

Catalyzed reactions (Rhea), 1 shown:

• H2O(in) = H2O(out) (RHEA:29667)

UniProt features (46 total): helix 11, topological domain 9, transmembrane region 6, sequence variant 6, strand 3, intramembrane region 2, short sequence motif 2, glycosylation site 2, mutagenesis site 2, turn 2, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3D9S	X-RAY DIFFRACTION	2
7STC	X-RAY DIFFRACTION	2.25
5C5X	X-RAY DIFFRACTION	2.6
5DYE	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55064-F1	93.58	0.87

Functional residue map

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

Glycosylation sites (2): 124, 125

Mutagenesis-validated functional residues (2):

Position	Phenotype
156	no effect on localization to plasma membrane.
156	increased localization to plasma membrane.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-432047	Passive transport by Aquaporins
R-HSA-382551	Transport of small molecules
R-HSA-445717	Aquaporin-mediated transport

MSigDB gene sets: 218 (showing top): MORF_RAGE, GOBP_DIGESTION, AP1_01, MORF_FLT1, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, MORF_MSH3, GOBP_PROTEIN_HOMOTETRAMERIZATION, GCANCTGNY_MYOD_Q6, MODULE_64, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MORF_ESR1, MODULE_16, CAGCTG_AP4_Q5

GO Biological Process (9): water transport (GO:0006833), carbon dioxide transport (GO:0015670), pancreatic juice secretion (GO:0030157), odontogenesis (GO:0042476), saliva secretion (GO:0046541), camera-type eye morphogenesis (GO:0048593), protein homotetramerization (GO:0051289), cellular hypotonic response (GO:0071476), transmembrane transport (GO:0055085)

GO Molecular Function (4): water channel activity (GO:0015250), identical protein binding (GO:0042802), protein binding (GO:0005515), channel activity (GO:0015267)

GO Cellular Component (9): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), microvillus (GO:0005902), basal plasma membrane (GO:0009925), apical plasma membrane (GO:0016324), cytoplasmic vesicle membrane (GO:0030659), extracellular exosome (GO:0070062), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
body fluid secretion	2
digestive system process	2
secretion by tissue	2
cytoplasm	2
plasma membrane region	2
fluid transport	1
gas transport	1
one-carbon compound transport	1
animal organ morphogenesis	1
camera-type eye development	1
eye morphogenesis	1
protein homooligomerization	1
protein tetramerization	1
hypotonic response	1
cellular response to osmotic stress	1
transport	1
cellular process	1
water transmembrane transporter activity	1
channel activity	1
protein binding	1
binding	1
passive transmembrane transporter activity	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
actin filament bundle	1
actin-based cell projection	1
basal part of cell	1
apical part of cell	1
vesicle membrane	1
cytoplasmic vesicle	1
extracellular vesicle	1
cellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

3044 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AQP5	TRPV4	Q9HBA0	854
AQP5	AQP12A	Q8IXF9	816
AQP5	AQP10	Q96PS8	812
AQP5	AQP11	Q8NBQ7	804
AQP5	SFTPC	P11686	799
AQP5	SCGB1A1	P11684	781
AQP5	KRT5	P13647	704
AQP5	SFTPB	P07988	671
AQP5	CDH1	P12830	666
AQP5	TJP1	Q07157	627
AQP5	SLC12A2	P55011	602
AQP5	PDPN	Q86YL7	584
AQP5	SFTPA2	P07714	581
AQP5	ABCA3	Q99758	572
AQP5	CTNNB1	P35222	569

IntAct

23 interactions, top by confidence:

A	B	Type	Score
AQP5	MDFI	psi-mi:“MI:0915”(physical association)	0.620
KRT31	AQP5	psi-mi:“MI:0915”(physical association)	0.560
KRT40	AQP5	psi-mi:“MI:0915”(physical association)	0.560
HNRNPK	AQP5	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	AQP5	psi-mi:“MI:0915”(physical association)	0.560
AQP5	KRT31	psi-mi:“MI:0915”(physical association)	0.560
AQP5	KRT40	psi-mi:“MI:0915”(physical association)	0.560
AQP5	HNRNPK	psi-mi:“MI:0915”(physical association)	0.560
AQP5	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
AQP5	AQP5	psi-mi:“MI:0407”(direct interaction)	0.560
AQP5	CREB3	psi-mi:“MI:0915”(physical association)	0.370
GLRX	AQP5	psi-mi:“MI:0915”(physical association)	0.370
WNT2	AQP5	psi-mi:“MI:0915”(physical association)	0.370
AQP5	ATP1A2	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): HNRNPK (Two-hybrid), KRT31 (Two-hybrid), KRT40 (Two-hybrid), NOTCH2NL (Two-hybrid), MDFI (Two-hybrid), AQP5 (Two-hybrid), ATP6V0A1 (Affinity Capture-MS), ATP1A2 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), MDFI (Two-hybrid), GLRX (Two-hybrid), WNT2 (Two-hybrid)

ESM2 similar proteins: A2IBY8, A4L9J0, A8W649, A9Y006, G5CTG2, G5CTG4, O43315, O62735, O77750, P06624, P09011, P29972, P29975, P30301, P34080, P41181, P47862, P47863, P47864, P47865, P50501, P51180, P55064, P55087, P55088, P56401, P56402, P56627, P79099, Q02013, Q06019, Q08DE6, Q13520, Q23808, Q5I4F9, Q5R819, Q6J8I9, Q6PQZ1, Q6RZ07, Q866S3

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

3 interactions.

A	Effect	B	Mechanism
PKA	“up-regulates activity”	AQP5	phosphorylation
PRKACA	“up-regulates activity”	AQP5	phosphorylation
AQP5	“up-regulates activity”	CyclinD/CDK4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	41
Likely benign	9
Benign	20

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
65478	NM_001651.4(AQP5):c.113C>A (p.Ala38Glu)	Pathogenic
65480	NM_001651.4(AQP5):c.134T>G (p.Ile45Ser)	Pathogenic
65481	NM_001651.4(AQP5):c.529A>T (p.Ile177Phe)	Pathogenic
65482	NM_001651.4(AQP5):c.367A>G (p.Asn123Asp)	Pathogenic
1172766	NM_001651.4(AQP5):c.526G>A (p.Gly176Arg)	Likely pathogenic

SpliceAI

703 predictions. Top by Δscore:

Variant	Effect	Δscore
12:49962376:ACGCG:A	donor_gain	1.0000
12:49962377:CGCG:C	donor_gain	1.0000
12:49962378:GCG:G	donor_gain	1.0000
12:49962378:GCGG:G	donor_gain	1.0000
12:49962379:CG:C	donor_gain	1.0000
12:49962380:GG:G	donor_gain	1.0000
12:49962381:G:A	donor_loss	1.0000
12:49962381:G:GG	donor_gain	1.0000
12:49963595:GCCCT:G	donor_gain	1.0000
12:49963654:GGA:G	donor_gain	1.0000
12:49963655:GA:G	donor_gain	1.0000
12:49963655:GAG:G	donor_gain	1.0000
12:49963657:G:GG	donor_gain	1.0000
12:49963661:GCA:G	donor_gain	1.0000
12:49963664:G:GG	donor_gain	1.0000
12:49964174:GG:G	donor_gain	1.0000
12:49964174:GGGTG:G	donor_loss	1.0000
12:49964175:GG:G	donor_gain	1.0000
12:49964175:GGTG:G	donor_loss	1.0000
12:49964176:G:GG	donor_gain	1.0000
12:49964176:GT:G	donor_loss	1.0000
12:49964177:T:A	donor_loss	1.0000
12:49964178:G:GT	donor_loss	1.0000
12:49963486:TTGCA:T	acceptor_loss	0.9900
12:49963488:GCAGC:G	acceptor_loss	0.9900
12:49963489:CA:C	acceptor_loss	0.9900
12:49963490:A:AC	acceptor_loss	0.9900
12:49963490:A:AG	acceptor_gain	0.9900
12:49963491:G:GG	acceptor_gain	0.9900
12:49963652:TCG:T	donor_gain	0.9900

AlphaMissense

1692 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:49964118:C:A	N185K	0.999
12:49964118:C:G	N185K	0.999
12:49962162:T:C	F49L	0.998
12:49962164:T:A	F49L	0.998
12:49962164:T:G	F49L	0.998
12:49962224:C:A	N69K	0.998
12:49962224:C:G	N69K	0.998
12:49964109:C:G	C182W	0.998
12:49963625:G:A	G166D	0.997
12:49963642:G:C	G172R	0.997
12:49963654:G:A	G176R	0.997
12:49963654:G:C	G176R	0.997
12:49963655:G:A	G176E	0.997
12:49964111:C:T	S183F	0.997
12:49964995:T:C	F206L	0.997
12:49964997:C:A	F206L	0.997
12:49964997:C:G	F206L	0.997
12:49964998:T:A	W207R	0.997
12:49964998:T:C	W207R	0.997
12:49962165:G:C	G50R	0.996
12:49962166:G:A	G50D	0.996
12:49962222:A:G	N69D	0.996
12:49962235:C:T	T73I	0.996
12:49962318:G:T	G101W	0.996
12:49962319:G:A	G101E	0.996
12:49963532:A:T	E135V	0.996
12:49963624:G:C	G166R	0.996
12:49963634:T:A	V169D	0.996
12:49964108:G:A	C182Y	0.996
12:49964125:C:A	R188S	0.996

dbSNP variants (sampled 300 via entrez): RS1000064706 (12:49961331 G>A), RS1000199363 (12:49965218 A>C,G), RS1000416428 (12:49963216 G>A), RS1002078821 (12:49964637 A>G), RS1003754606 (12:49965532 T>C,G), RS1003764614 (12:49965268 C>T), RS1004377671 (12:49960863 G>C), RS1004380469 (12:49964394 A>C), RS1004647066 (12:49965709 G>T), RS1005910722 (12:49964708 T>G), RS1006077654 (12:49966169 G>C,T), RS1007386532 (12:49964493 T>G), RS1007607364 (12:49961441 G>A), RS1007934281 (12:49963794 G>A), RS1008005067 (12:49961987 C>A)

Disease associations

OMIM: gene MIM:600442 | disease phenotypes: MIM:600231

GenCC curated gene-disease

Disease	Classification	Inheritance
palmoplantar keratoderma, Bothnian type	Strong	Autosomal dominant
nonepidermolytic palmoplantar keratoderma	Supportive	Autosomal dominant

Mondo (2): palmoplantar keratoderma, Bothnian type (MONDO:0010849), (MONDO:0006588)

Orphanet (1): Diffuse palmoplantar keratoderma, Bothnian type (Orphanet:2337)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000975	Hyperhidrosis
HP:0000989	Pruritus
HP:0001807	Ridged nail
HP:0007447	Diffuse palmoplantar hyperkeratosis
HP:0008066	Abnormal blistering of the skin
HP:0010783	Erythema
HP:0011463	Childhood onset
HP:0032259	Chronic tinea infection
HP:0032541	Knuckle pad
HP:0200034	Papule
HP:0200042	Skin ulcer

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006409_17	Allergic rhinitis	5.000000e-10
GCST010043_56	Asthma	5.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523244 (SINGLE PROTEIN)

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

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases expression, decreases expression, increases abundance, decreases reaction, affects cotreatment (+1 more)	3
Air Pollutants	decreases expression, increases abundance, increases expression	2
Vehicle Emissions	decreases reaction, increases abundance, affects cotreatment, decreases abundance, increases expression (+1 more)	2
Histamine	decreases expression, decreases reaction, affects localization	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
naringenin	increases abundance, decreases expression, decreases reaction	1
bisphenol A	decreases expression	1
butyraldehyde	increases expression	1
cordycepin	decreases expression, decreases reaction, increases expression	1
prolinedithiocarbamate	decreases expression, decreases reaction	1
Roflumilast	decreases expression, decreases reaction, increases abundance	1
2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide	increases expression, decreases reaction	1
Allergens	decreases abundance, increases expression, affects cotreatment	1
Amphotericin B	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Calcitriol	decreases expression	1
Carbachol	affects localization	1
Estradiol	increases expression	1
Hydrogen Peroxide	decreases reaction, decreases expression	1
Smoke	increases abundance, increases expression	1
Valproic Acid	increases methylation	1
Zearalenone	increases expression	1
Lactic Acid	decreases expression	1
Glycyrrhizic Acid	decreases expression, decreases reaction	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4422159	Binding	Inhibition of AQP5 (unknown origin) expressed in CHO cells assessed as reduction in aquaporin-mediated cell Volume shrinkage at 10 uM by light scattering based assay	Novel prodrug salts

Clinical trials (associated diseases)

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