PKD2L1

Summary

PKD2L1 (polycystin 2 like 1, transient receptor potential cation channel, HGNC:9011) is a protein-coding gene on chromosome 10q24.31, encoding Polycystin-2-like protein 1 (Q9P0L9). Homotetrameric, non-selective cation channel that is permeable to sodium, potassium, magnesium and calcium.

This gene encodes a member of the polycystin protein family. The encoded protein contains multiple transmembrane domains, and cytoplasmic N- and C-termini. The protein may be an integral membrane protein involved in cell-cell/matrix interactions. This protein functions as a calcium-regulated nonselective cation channel. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9033 — RefSeq curated summary.

At a glance

• GWAS associations: 34
• Clinical variants (ClinVar): 139 total
• MANE Select transcript: NM_016112

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9011
Approved symbol	PKD2L1
Name	polycystin 2 like 1, transient receptor potential cation channel
Location	10q24.31
Locus type	gene with protein product
Status	Approved
Aliases	PCL, TRPP3
Ensembl gene	ENSG00000107593
Ensembl biotype	protein_coding
OMIM	604532
Entrez	9033

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 nonsense_mediated_decay

ENST00000318222, ENST00000465680, ENST00000528248, ENST00000532547

RefSeq mRNA: 2 — MANE Select: NM_016112 NM_001253837, NM_016112

CCDS: CCDS7492

Canonical transcript exons

ENST00000318222 — 16 exons

Exon	Start	End
ENSE00000987502	100329869	100330228
ENSE00001886051	100288149	100288478
ENSE00003496092	100298562	100298815
ENSE00003507138	100293281	100293379
ENSE00003508370	100296122	100296292
ENSE00003551767	100290015	100290138
ENSE00003554690	100288972	100289056
ENSE00003556177	100299591	100299718
ENSE00003561221	100294942	100295123
ENSE00003591438	100296980	100297208
ENSE00003615411	100329211	100329324
ENSE00003645459	100292948	100293069
ENSE00003647500	100290401	100290519
ENSE00003651408	100294535	100294655
ENSE00003654806	100291301	100291427
ENSE00003694206	100297382	100297606

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 83.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0761 / max 66.0241, expressed in 28 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111043	0.0445	14
111042	0.0315	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	83.45	silver quality
spleen	UBERON:0002106	80.10	gold quality
pancreatic ductal cell	CL:0002079	77.88	silver quality
triceps brachii	UBERON:0001509	75.19	gold quality
gluteal muscle	UBERON:0002000	74.41	gold quality
endothelial cell	CL:0000115	73.10	gold quality
right frontal lobe	UBERON:0002810	73.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.70	gold quality
cervix squamous epithelium	UBERON:0006922	72.20	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	71.65	gold quality
blood vessel layer	UBERON:0004797	71.18	silver quality
nephron tubule	UBERON:0001231	70.43	gold quality
sperm	CL:0000019	70.17	silver quality
renal glomerulus	UBERON:0000074	69.93	silver quality
upper leg skin	UBERON:0004262	69.72	silver quality
right lung	UBERON:0002167	68.63	gold quality
oocyte	CL:0000023	68.61	gold quality
male germ cell	CL:0000015	68.60	silver quality
tibia	UBERON:0000979	67.67	gold quality
orbitofrontal cortex	UBERON:0004167	67.62	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	66.86	gold quality
frontal cortex	UBERON:0001870	66.62	gold quality
anterior cingulate cortex	UBERON:0009835	66.57	gold quality
cingulate cortex	UBERON:0003027	66.50	gold quality
hair follicle	UBERON:0002073	66.13	gold quality
neocortex	UBERON:0001950	65.52	gold quality
cerebral cortex	UBERON:0000956	65.47	gold quality
layer of synovial tissue	UBERON:0007616	65.41	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	65.22	gold quality
prefrontal cortex	UBERON:0000451	64.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting PKD2L1, 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-3688-3P	99.97	72.02	2834
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-5187-3P	97.28	67.10	1037

Literature-anchored findings (GeneRIF, showing 19)

• The calcium-binding EF-hand in polycystin-L is not a domain for channel activation and ensuing inactivation. (PMID:11959145)
• Taken together, alpha-actinin not only attaches TRPP3 to the cytoskeleton but also up-regulates TRPP3 channel function. (PMID:17944866)
• the PKD2L1-PKD1L3 complex is involved in acid sensing in vivo (PMID:20406802)
• Despite the moderate sequence identity between C-terminal regulatory domains (CRDs) of PKD2 and PKD2L1, they both form trimers, implying that trimeric organization of CRDs may be true of all polycystin channels. (PMID:20408813)
• Pkd2L1 is a novel target channel whose function is regulated by the versatile scaffolding protein RACK1. (PMID:22174419)
• Trimerization may be important for both homo- and possibly heteromeric assemblies of PKD2L1. (PMID:22193359)
• This study demonistrated that human PKD2L play the role of food preference behavior. (PMID:22794107)
• our study identified C1 as the first PKD2L1 domain essential for both PKD2L1 trimerization and channel function, and suggest that PKD2L1 and PKD2L1/PKD1L3 channels share the PKD2L1 trimerization process. (PMID:25820328)
• palmitoylation at Cys-38 and phosphorylation at Thr-39 independently regulated TRPP3 channel function (PMID:27754867)
• Charge-neutralizing mutations (K452Q, K455Q and K461Q) in transmembrane segment 4 reduced gating charges, positively shifted the Boltzmann-type activation curve [i.e., open probability (P open)-V curve] and altered the time-courses of activation/deactivation of PKD2L1, indicating that this region constitutes part of a voltage sensor. (PMID:28852171)
• Clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 are significant for the channel regulation by phosphorylation. (PMID:29230552)
• The pore helix and transmembrane segment 6 of PKD2L1 are involved in upper and lower-gate opening, adopt an open conformation. (PMID:29567962)
• PKD2 and PKD1 genes are mutated in autosomal dominant polycystic kidney disease. PKD2 can form either a homomeric cation channel or a heteromeric complex with the PKD1 receptor, presumed to respond to ligand(s) and/or mechanical stimuli. Here, we identify a two-residue hydrophobic gate in PKD2L1, and a single-residue hydrophobic gate in PKD2. (PMID:29899465)
• The related primary cilium-specific polycystin-2 protein, encoded by PKD2, shares a high degree of sequence similarity, yet has distinct permeability characteristics. Here the authors show that these differences are reflected in the architecture of polycystin 2-l1. (PMID:30004384)
• Opening TRPP2 (PKD2L1) requires the transfer of gating charges. (PMID:31315976)
• Adaptive selection drives TRPP3 loss-of-function in an Ethiopian population. (PMID:33268808)
• Molecular Mechanism of L-Pyroglutamic Acid Interaction with the Human Sour Receptor. (PMID:36655284)
• Polycystic kidney disease 2-like 1 channel contributes to the bitter aftertaste perception of quinine. (PMID:36922541)
• Genetic Variants in WNT16 and PKD2L1 Locus Affect Heel Ultrasound Bone Stiffness: Analyses from the General Population and Patients Evaluated for Osteoporosis. (PMID:37831088)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pkd2l1	ENSDARG00000022503
mus_musculus	Pkd2l1	ENSMUSG00000037578
rattus_norvegicus	Pkd2l1	ENSRNOG00000012591

Paralogs (10): PKD1 (ENSG00000008710), PKD2L2 (ENSG00000078795), PKD2 (ENSG00000118762), PKDREJ (ENSG00000130943), PKD1L1 (ENSG00000158683), PKD1L2 (ENSG00000166473), LOXHD1 (ENSG00000167210), DENND5B (ENSG00000170456), DENND5A (ENSG00000184014), PKD1L3 (ENSG00000277481)

Protein

Protein identifiers

Polycystin-2-like protein 1 — Q9P0L9 (reviewed: Q9P0L9)

Alternative names: Polycystic kidney disease 2-like 1 protein, Polycystin-2 homolog, Polycystin-L, Polycystin-L1

All UniProt accessions (4): Q9P0L9, E9PRD1, H0YDN7, H0YET4

UniProt curated annotations — full annotation on UniProt →

Function. Homotetrameric, non-selective cation channel that is permeable to sodium, potassium, magnesium and calcium. Also forms functional heteromeric channels with PKD1, PKD1L1 and PKD1L3. Pore-forming subunit of a heterotetrameric, non-selective cation channel, formed by PKD1L2 and PKD1L3, that is permeable to sodium, potassium, magnesium and calcium and which may act as a sour taste receptor in gustatory cells; however, its contribution to sour taste perception is unclear in vivo and may be indirect. The homomeric and heteromeric channels formed by PKD1L2 and PKD1L3 are activated by low pH and Ca(2+), but opens only when the extracellular pH rises again and after the removal of acid stimulus. Pore-forming subunit of a calcium-permeant ion channel formed by PKD1L2 and PKD1L1 in primary cilia, where it controls cilium calcium concentration, without affecting cytoplasmic calcium concentration, and regulates sonic hedgehog/SHH signaling and GLI2 transcription. The PKD1L1:PKD2L1 complex channel is mechanosensitive only at high pressures and is highly temperature sensitive. Pore-forming subunit of a calcium-permeant ion channel formed by PKD1L2 and PKD1 that produces a transient increase in intracellular calcium concentration upon hypo-osmotic stimulation (200 mOsm). May play a role in the perception of carbonation taste. May play a role in the sensory perception of water, via a mechanism that activates the channel in response to dilution of salivary bicarbonate and changes in salivary pH.

Subunit / interactions. Oligomer. Functional PKD2L1 homotetramer can be formed either through C-terminal trimerization followed by N-terminal dimerization of a fourth subunit with a subunit in the trimer or through dimerization followed by trimerization. Heterotetramer with either PKD1L1, PKD1L3 or PKD1; the heterotetrameric complex contains three PKD1L2 chains plus one chain from another family member. Interacts with PKD1L1, forming a ciliary calcium channel. Interacts with PKD1L3, forming a cation channel that is activated by low extracellular pH. Interacts with PKD1; this heteromeric functional cation channels is opened by hypo-osmotic stimulation. Interacts with RACK1; inhibits the channel activity possibly by impairing localization to the cell membrane.

Subcellular location. Cell projection. Cilium membrane. Cell membrane. Cytoplasmic vesicle.

Tissue specificity. Detected in taste bud cells in fungiform papillae (at protein level). Ubiquitous. Expressed in adult heart, skeletal muscle, brain, spleen, testis, retina and liver. Isoform 4 appears to be expressed only in transformed lymphoblasts.

Post-translational modifications. Palmitoylation is important for expression at the cell membrane and for channel activity.

Activity regulation. The non-selective cation channel is gated following an off-response property by acid: gated open after the removal of acid stimulus, but not during acid application. Channel activity is inhibited by phosphatidylinositol-4,5-bisphosphate (PIP2). Non-selective cation channel activity is substantially increased when either the extracellular or intracellular calcium-ion concentration is raised. Regulation of non-selective cation channel activity by external calcium is bimodal, first sensitizing and subsequently inactivating the current.

Domain organisation. The EF-hand domain is not required for channel activation. Interaction of the cytoplasmic N- and C-terminal domains is important for the non-selective cation channel activity.

Miscellaneous. Unusual intron exon spliced junction.

Similarity. Belongs to the polycystin family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9P0L9-1	1	yes
Q9P0L9-2	2, PKDLdel15, PCL-TS, Testis isoform
Q9P0L9-3	3, PKDLdel5
Q9P0L9-4	4, PKDLdel456
Q9P0L9-5	5, PCL-LV, Liver isoform

RefSeq proteins (2): NP_001240766, NP_057196* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003915	PKD_2	Family
IPR013122	PKD1_2_channel	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR046791	Polycystin_dom	Domain
IPR051223	Polycystin	Family

Pfam: PF08016, PF18109, PF20519

Catalyzed reactions (Rhea), 4 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Mg(2+)(in) = Mg(2+)(out) (RHEA:29827)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (104 total): mutagenesis site 26, helix 15, strand 14, topological domain 8, transmembrane region 6, splice variant 5, sequence variant 5, turn 5, binding site 4, glycosylation site 4, region of interest 3, coiled-coil region 2, chain 1, intramembrane region 1, domain 1, compositionally biased region 1, lipid moiety-binding region 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3TE3	X-RAY DIFFRACTION	2.69
4GIF	X-RAY DIFFRACTION	2.8
6DU8	ELECTRON MICROSCOPY	3.11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0L9-F1	76.09	0.38

Functional residue map

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

Ligand- & substrate-binding residues (4): 370; 373; 387; 390

Post-translational modifications (1): 38

Disulfide bonds (1): 210–223

Glycosylation sites (4): 177, 207, 241, 505

Mutagenesis-validated functional residues (26):

Position	Phenotype
2–96	loss of channel activity. no effect on expression at the cell membrane.
2–38	loss of channel activity.
2–36	no effect on channel activity.
38	strongly decreased channel activity. no effect on expression at the cell membrane. loss of palmitoylation.
39	decreased channel activity.
81–95	loss of channel activity.
81	loss of channel activity. no effect on expression at the cell membrane.
523–525	abolishes ion channel activity.
523	increased permeability of dimethylamine and trimethylamine and decreased permeability of magnesium.
525	increased permeability of dimethylamine and trimethylamine and decreased permeability of magnesium.
530	does not affect ion channel activity.
566–805	loss of channel activity. no effect on expression at the cell membrane.
568	loss of channel activity.
581–805	loss of channel activity. no effect on expression at the cell membrane.
594–599	loss of phosphatidylinositol-4,5-bisphosphate binding.
594	increased channel activity.
596	increased channel activity.
598	mildly increased channel activity.
599	mildly increased channel activity.
622–805	no effect on channel activity. no effect on expression at the cell membrane.
710	abolishes homooligomer formation; when associated with a-714; a-717; a-728; a-731 and a-735.
714	abolishes homooligomer formation; when associated with a-710; a-717; a-728; a-731 and a-735.
717	abolishes homooligomer formation; when associated with a-710; a-714; a-728; a-731 and a-735.
728	abolishes homooligomer formation; when associated with a-710; a-714; a-717; a-731 and a-735.
731	abolishes homooligomer formation; when associated with a-710; a-714; a-717; a-728 and a-735.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 120 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GCANCTGNY_MYOD_Q6, MODULE_511, GOCC_CELL_SURFACE, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_DETECTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_CHEMICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION_OF_TASTE, GOBP_SENSORY_PERCEPTION_OF_TASTE, HEN1_01, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (19): detection of chemical stimulus involved in sensory perception of sour taste (GO:0001581), monoatomic cation transport (GO:0006812), smoothened signaling pathway (GO:0007224), response to water (GO:0009415), sodium ion transmembrane transport (GO:0035725), detection of chemical stimulus involved in sensory perception of taste (GO:0050912), sensory perception of sour taste (GO:0050915), detection of mechanical stimulus (GO:0050982), protein homotetramerization (GO:0051289), cellular response to acidic pH (GO:0071468), potassium ion transmembrane transport (GO:0071805), monoatomic cation transmembrane transport (GO:0098655), obsolete inorganic cation transmembrane transport (GO:0098662), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), protein tetramerization (GO:0051262), calcium ion transmembrane transport (GO:0070588), cellular response to pH (GO:0071467)

GO Molecular Function (19): calcium-activated cation channel activity (GO:0005227), monoatomic cation channel activity (GO:0005261), calcium channel activity (GO:0005262), sodium channel activity (GO:0005272), calcium ion binding (GO:0005509), cytoskeletal protein binding (GO:0008092), calcium-activated potassium channel activity (GO:0015269), sour taste receptor activity (GO:0033040), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), muscle alpha-actinin binding (GO:0051371), alpha-actinin binding (GO:0051393), pH-gated monoatomic ion channel activity (GO:0160128), osmolarity-sensing monoatomic cation channel activity (GO:1990760), protein binding (GO:0005515), monoatomic cation transmembrane transporter activity (GO:0008324), actinin binding (GO:0042805), metal ion binding (GO:0046872), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (15): endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), actin cytoskeleton (GO:0015629), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), calcium channel complex (GO:0034704), signaling receptor complex (GO:0043235), ciliary membrane (GO:0060170), non-motile cilium (GO:0097730), cytoplasm (GO:0005737), cilium (GO:0005929), cation channel complex (GO:0034703), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
monoatomic cation transmembrane transport	4
monoatomic cation channel activity	3
protein binding	3
cytoplasm	3
monoatomic ion transport	2
sensory perception of taste	2
metal ion transport	2
monoatomic cation transmembrane transporter activity	2
cilium	2
detection of chemical stimulus involved in sensory perception of taste	1
sensory perception of sour taste	1
cell surface receptor signaling pathway	1
response to acid chemical	1
response to abiotic stimulus	1
response to oxygen-containing compound	1
sodium ion transport	1
detection of chemical stimulus involved in sensory perception	1
detection of external stimulus	1
detection of abiotic stimulus	1
response to mechanical stimulus	1
protein homooligomerization	1
protein tetramerization	1
response to acidic pH	1
cellular response to pH	1
potassium ion transport	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
transport	1
transmembrane transport	1
protein complex oligomerization	1
calcium ion transport	1
response to pH	1
cellular response to abiotic stimulus	1
monoatomic ion-gated channel activity	1
ligand-gated monoatomic cation channel activity	1
monoatomic ion channel activity	1
calcium ion transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
metal ion binding	1

Protein interactions and networks

STRING

1024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PKD2L1	PKD1L3	Q7Z443	989
PKD2L1	PKD1L1	Q8TDX9	984
PKD2L1	TRPM5	Q9NZQ8	947
PKD2L1	TRPC1	P48995	755
PKD2L1	PLCB2	Q00722	728
PKD2L1	CA4	P22748	723
PKD2L1	TAS1R1	Q7RTX1	719
PKD2L1	OTOP1	Q7RTM1	718
PKD2L1	PKD1	P98161	707
PKD2L1	TAS1R2	Q8TE23	688
PKD2L1	TAS1R3	Q7RTX0	673
PKD2L1	GNAT3	A8MTJ3	653
PKD2L1	TRPA1	O75762	636
PKD2L1	TRPM4	Q8TD43	621
PKD2L1	MCOLN1	Q9GZU1	619

IntAct

5 interactions, top by confidence:

A	B	Type	Score
CLDN19	PKD2L1	psi-mi:“MI:0915”(physical association)	0.560
PKD1L3	PKD2L1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (6): PKD2L1 (Two-hybrid), TNNI3 (Affinity Capture-Western), TNNI1 (Reconstituted Complex), TNNI3 (Reconstituted Complex), TNNI3 (Two-hybrid), PKD2L1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A1A5B4, A2AHL1, A2BIE7, A2RRU4, A5PK40, A6NDV4, A6QLK4, A6QM06, B1AWJ5, E9PTA2, E9Q6C8, O94759, P86044, P97260, Q04671, Q12770, Q17QL9, Q3TD49, Q49LS8, Q4R7X9, Q5F383, Q5GH57, Q5MNU5, Q5PQL3, Q5RBY7, Q5ZMP3, Q60HE8, Q6AY05, Q6GQT6, Q6UX01, Q7RTT9, Q7TN60, Q7Z403, Q8IU68, Q8MIQ9, Q8N4M1, Q8R139, Q8R4F0, Q8TCT7, Q91YD4

Diamond homologs: A2A259, H2LRU7, O35245, Q13563, Q4GZT3, Q6IVV8, Q9HCX4, Q9JLG4, Q9NZM6, Q9P0L9, Q9U1S7, Q9WVC5, Q7TN88, Q9JMI9, Q9QZC1, Q13507

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PRKACA	“up-regulates activity”	PKD2L1	phosphorylation
CAMK2A	“down-regulates activity”	PKD2L1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	10
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

2984 predictions. Top by Δscore:

Variant	Effect	Δscore
10:100288996:C:A	donor_gain	1.0000
10:100291299:AC:A	donor_gain	1.0000
10:100291300:CC:C	donor_gain	1.0000
10:100291300:CCCT:C	donor_gain	1.0000
10:100291308:T:TA	donor_gain	1.0000
10:100291424:CAGT:C	acceptor_gain	1.0000
10:100291428:C:CC	acceptor_gain	1.0000
10:100292946:A:AC	donor_gain	1.0000
10:100292946:ACT:A	donor_gain	1.0000
10:100292946:ACTCC:A	donor_gain	1.0000
10:100292947:C:CC	donor_gain	1.0000
10:100292947:CT:C	donor_gain	1.0000
10:100292947:CTC:C	donor_gain	1.0000
10:100292947:CTCCC:C	donor_gain	1.0000
10:100292950:C:A	donor_gain	1.0000
10:100293276:ATCAC:A	donor_loss	1.0000
10:100293277:TCACC:T	donor_loss	1.0000
10:100293278:CA:C	donor_loss	1.0000
10:100293279:A:AT	donor_loss	1.0000
10:100293280:C:CT	donor_loss	1.0000
10:100293378:TT:T	acceptor_gain	1.0000
10:100293380:C:CC	acceptor_gain	1.0000
10:100295144:C:CT	acceptor_gain	1.0000
10:100295145:A:T	acceptor_gain	1.0000
10:100296117:GGTAC:G	donor_loss	1.0000
10:100296118:GTAC:G	donor_loss	1.0000
10:100296119:TACCT:T	donor_loss	1.0000
10:100296120:A:AT	donor_loss	1.0000
10:100296121:C:CT	donor_loss	1.0000
10:100296264:A:C	acceptor_gain	1.0000

AlphaMissense

5289 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:100295040:G:C	F480L	0.998
10:100295040:G:T	F480L	0.998
10:100295042:A:G	F480L	0.998
10:100295005:G:T	A492D	0.997
10:100296130:A:G	W450R	0.997
10:100296130:A:T	W450R	0.997
10:100293366:G:T	A558D	0.996
10:100295011:G:T	A490D	0.996
10:100295038:G:T	A481D	0.996
10:100295039:C:G	A481P	0.996
10:100293363:A:T	I559N	0.995
10:100294584:C:T	G537D	0.995
10:100295006:C:G	A492P	0.995
10:100295063:A:G	C473R	0.995
10:100295083:A:G	L466P	0.995
10:100293360:A:T	I560N	0.994
10:100294542:A:T	V551E	0.994
10:100294632:A:G	L521P	0.994
10:100294990:A:G	L497P	0.994
10:100294996:C:T	G495D	0.994
10:100294997:C:G	G495R	0.994
10:100295028:G:C	F484L	0.994
10:100295028:G:T	F484L	0.994
10:100295030:A:G	F484L	0.994
10:100295032:A:C	M483R	0.994
10:100295032:A:T	M483K	0.994
10:100295061:A:C	C473W	0.994
10:100295062:C:T	C473Y	0.994
10:100295071:A:G	L470P	0.994
10:100295074:G:T	T469K	0.994

dbSNP variants (sampled 300 via entrez): RS1000107175 (10:100298056 G>C), RS1000233345 (10:100302472 G>A), RS1000291608 (10:100296587 C>G), RS1000319353 (10:100296797 G>A,C), RS1000323150 (10:100324644 G>A), RS1000344550 (10:100310441 C>T), RS1000351280 (10:100303872 G>T), RS1000379343 (10:100310722 T>C), RS1000479317 (10:100298478 C>G,T), RS1000496737 (10:100303548 C>G), RS1000627559 (10:100297771 T>C), RS1000851580 (10:100291625 C>A,T), RS1001070151 (10:100308582 A>C,G), RS1001086009 (10:100328970 C>T), RS1001152322 (10:100316019 C>G,T)

Disease associations

OMIM: gene MIM:604532 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST001414_13	Phospholipid levels (plasma)	6.000000e-14
GCST001762_671	Obesity-related traits	2.000000e-06
GCST001838_1	Palmitic acid (16:0) levels	2.000000e-07
GCST001841_14	Palmitoleic acid (16:1n-7) levels	6.000000e-15
GCST002388_14	Serum metabolite levels	1.000000e-11
GCST003830_49	Response to bronchodilator in chronic obstructive pulmonary disease (change in FEV1)	7.000000e-07
GCST003830_56	Response to bronchodilator in chronic obstructive pulmonary disease (change in FEV1)	2.000000e-09
GCST004339_2	Palmitoleic acid (16:1n-7) levels	4.000000e-15
GCST004342_1	Vaccenic acid (18:1n-7) levels	6.000000e-17
GCST004342_3	Vaccenic acid (18:1n-7) levels	2.000000e-16
GCST004599_8	Mean platelet volume	5.000000e-31
GCST004750_29	Squamous cell lung carcinoma	1.000000e-06
GCST005194_187	Coronary artery disease	3.000000e-06
GCST005650_208	Serum metabolite ratios in chronic kidney disease	3.000000e-13
GCST006288_638	Heel bone mineral density	3.000000e-12
GCST006288_721	Heel bone mineral density	3.000000e-09
GCST006630_22	Diastolic blood pressure	2.000000e-17
GCST006976_55	Macular thickness	2.000000e-10
GCST006979_602	Heel bone mineral density	4.000000e-41
GCST007636_2	Fatty acid desaturase activity (adipose tissue)	2.000000e-19
GCST009240_21	Serum metabolite levels (CMS)	7.000000e-11
GCST010002_298	Refractive error	3.000000e-22
GCST010204_143	Low density lipoprotein cholesterol levels	3.000000e-11
GCST010866_146	Coronary artery disease	6.000000e-09
GCST012020_24	Serum metabolite levels	2.000000e-14
GCST012020_419	Serum metabolite levels	2.000000e-13
GCST012020_420	Serum metabolite levels	2.000000e-15
GCST012020_421	Serum metabolite levels	3.000000e-17
GCST90002388_573	Lymphocyte count	4.000000e-14
GCST90002395_33	Mean platelet volume	1.000000e-71

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0005119	antioxidant measurement
EFO:0005921	FEV change measurement
EFO:0007973	palmitoleic acid measurement
EFO:0007974	vaccenic acid measurement
EFO:0009270	heel bone mineral density
EFO:0006336	diastolic blood pressure
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004587	lymphocyte count
EFO:0009188	Red cell distribution width
EFO:0004533	alkaline phosphatase measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

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: vgic — Transient Receptor Potential channels (TRP)

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
phenamil	Channel blocker	6.9	pIC50
benzamil	Channel blocker	6.0	pIC50
ethylisopropylamiloride	Channel blocker	5.0	pIC50
amiloride	Channel blocker	3.8	pIC50
HCl	Agonist	1.89	pEC50
citric acid	Agonist	1.7	pEC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
Estradiol	affects binding, increases expression, affects cotreatment	2
propionaldehyde	increases expression	1
terbufos	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Azacitidine	increases expression	1
Catechin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Bucladesine	affects cotreatment, increases expression	1
Fonofos	increases methylation	1
Indomethacin	affects cotreatment, increases expression	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Rifampin	decreases expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
2,4-Dichlorophenoxyacetic Acid	decreases expression	1
Medroxyprogesterone Acetate	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer