TPCN1

Summary

TPCN1 (two pore segment channel 1, HGNC:18182) is a protein-coding gene on chromosome 12q24.13, encoding Two pore channel protein 1 (Q9ULQ1). Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a voltage-gated highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisph….

Voltage-gated Ca(2+) and Na+ channels have 4 homologous domains, each containing 6 transmembrane segments, S1 to S6. TPCN1 is similar to these channels, but it has only 2 domains containing S1 to S6 (Ishibashi et al., 2000 [PubMed 10753632]).

Source: NCBI Gene 53373 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 118 total
• MANE Select transcript: NM_017901

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18182
Approved symbol	TPCN1
Name	two pore segment channel 1
Location	12q24.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1169, FLJ20612, TPC1
Ensembl gene	ENSG00000186815
Ensembl biotype	protein_coding
OMIM	609666
Entrez	53373

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 42 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000335509, ENST00000392569, ENST00000428632, ENST00000541517, ENST00000546503, ENST00000546781, ENST00000546787, ENST00000546907, ENST00000547275, ENST00000547955, ENST00000548465, ENST00000549279, ENST00000550543, ENST00000550785, ENST00000550873, ENST00000551096, ENST00000551099, ENST00000551127, ENST00000552077, ENST00000552542, ENST00000552642, ENST00000552897, ENST00000552985, ENST00000879862, ENST00000879863, ENST00000879864, ENST00000879865, ENST00000879866, ENST00000879867, ENST00000879868, ENST00000879869, ENST00000879870, ENST00000879871, ENST00000879872, ENST00000879873, ENST00000879874, ENST00000879875, ENST00000879876, ENST00000879877, ENST00000879878, ENST00000879879, ENST00000879880, ENST00000879881, ENST00000933067, ENST00000933068, ENST00000933069, ENST00000971651, ENST00000971652, ENST00000971653, ENST00000971654

RefSeq mRNA: 5 — MANE Select: NM_017901 NM_001143819, NM_001301214, NM_001351346, NM_001351347, NM_017901

CCDS: CCDS31908, CCDS44985, CCDS76605

Canonical transcript exons

ENST00000335509 — 28 exons

Exon	Start	End
ENSE00000562946	113288163	113288234
ENSE00002354875	113295960	113298585
ENSE00002381287	113221464	113221626
ENSE00003460290	113273569	113273668
ENSE00003470047	113284581	113284637
ENSE00003477957	113293269	113293349
ENSE00003487739	113280151	113280195
ENSE00003509913	113278189	113278237
ENSE00003519993	113260368	113260492
ENSE00003520547	113292934	113293073
ENSE00003543220	113291874	113291958
ENSE00003549094	113290128	113290243
ENSE00003549744	113269757	113269845
ENSE00003553645	113226728	113226964
ENSE00003571817	113273232	113273290
ENSE00003577693	113290952	113290998
ENSE00003581253	113266180	113266356
ENSE00003587993	113272658	113272692
ENSE00003594067	113288758	113288847
ENSE00003642949	113268742	113268872
ENSE00003650204	113285889	113285961
ENSE00003665067	113278772	113278835
ENSE00003667804	113276919	113277035
ENSE00003668416	113284718	113284771
ENSE00003679288	113277240	113277364
ENSE00003680840	113291609	113291677
ENSE00003689638	113286987	113287094
ENSE00003692294	113267843	113267956

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 98.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.3586 / max 451.1032, expressed in 1812 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128158	36.6216	1812
128161	0.2222	70
128162	0.2123	63
128168	0.0722	44
128169	0.0640	29
128170	0.0489	18
128167	0.0393	11
206905	0.0221	8
128165	0.0203	4
128164	0.0124	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.05	gold quality
cerebellar hemisphere	UBERON:0002245	97.88	gold quality
cerebellar cortex	UBERON:0002129	97.84	gold quality
right lobe of thyroid gland	UBERON:0001119	97.53	gold quality
cerebellum	UBERON:0002037	97.50	gold quality
left lobe of thyroid gland	UBERON:0001120	97.13	gold quality
mucosa of stomach	UBERON:0001199	97.05	gold quality
apex of heart	UBERON:0002098	97.03	gold quality
metanephros cortex	UBERON:0010533	96.99	gold quality
thyroid gland	UBERON:0002046	96.78	gold quality
right adrenal gland	UBERON:0001233	96.69	gold quality
right adrenal gland cortex	UBERON:0035827	96.64	gold quality
body of pancreas	UBERON:0001150	96.56	gold quality
adrenal cortex	UBERON:0001235	96.35	gold quality
left adrenal gland cortex	UBERON:0035825	96.29	gold quality
left ovary	UBERON:0002119	96.27	gold quality
right uterine tube	UBERON:0001302	96.21	gold quality
left adrenal gland	UBERON:0001234	96.18	gold quality
right ovary	UBERON:0002118	95.98	gold quality
lower esophagus mucosa	UBERON:0035834	95.88	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.84	gold quality
minor salivary gland	UBERON:0001830	95.68	gold quality
right coronary artery	UBERON:0001625	95.64	gold quality
left ventricle myocardium	UBERON:0006566	95.61	gold quality
descending thoracic aorta	UBERON:0002345	95.59	gold quality
adrenal gland	UBERON:0002369	95.53	gold quality
heart left ventricle	UBERON:0002084	95.50	gold quality
cardiac ventricle	UBERON:0002082	95.37	gold quality
sural nerve	UBERON:0015488	95.30	gold quality
cardiac atrium	UBERON:0002081	95.20	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	48.62
E-MTAB-9067	yes	11.20
E-MTAB-7303	no	171.41
E-GEOD-124858	no	75.09
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

103 targeting TPCN1, 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-8485	100.00	77.57	4731
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
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-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-448	99.79	72.37	2103

Literature-anchored findings (GeneRIF, showing 15)

• Data show that human two-pore channel TPC1 is critical for nicotinic acid adenine dinucleotide phosphate action and is likely the long sought after target channel for NAADP. (PMID:19620632)
• OsTPC1 plays a crucial role in TvX-induced Ca(2+) influx as a plasma membrane Ca(2+)-permeable channel consequently required for the regulation of phytoalexin biosynthesis (PMID:22270358)
• The concerted regulation of TPC1 activity by luminal Ca(2+) and by membrane potential thus provides a potential mechanism to explain NAADP-induced Ca(2+) oscillations. (PMID:22500018)
• TPC1 is a member of a new family of voltage-gated Na(+) channels that senses pH changes and confers electrical excitability to organelles. (PMID:24776928)
• NAADP triggers H+ release from lysosomes and endolysomes through activation of TPC1, but that the Ca2+ -releasing ability of TPC1 will depend on the ionic composition of the acidic stores (PMID:24847115)
• TPC2, but not TPC1, caused a proliferation of endolysosomal structures, dysregulating intracellular trafficking, and cellular pigmentation. (PMID:25157141)
• NAADP induced marked Ca(2+) transients in HEK293 cells that stably coexpressed hTPC2 with hTPC1 or cTPC3, but failed to evoke any such response in cells that coexpressed interacting hTPC2 and rTPC3 subunits (PMID:25451935)
• The TPC1 was shown to interact with citron kinase, with TPC1 overexpression affecting RhoA activity and myosin light chain phosphorylation levels in cytokinesis. (PMID:25665131)
• TPC1 and TPC2 proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy. (PMID:25722412)
• Studies suggest that both two-pore channels TPC1 and TPC2 as nicotinic acid adenine dinucleotide phosphate (NAADP) targets. (PMID:26152696)
• These findings indicate potential differential regulation of signaling processes by TPC1 and TPC2 in breast cancer cells. (PMID:27353380)
• These data point to a process in which Ca(2+) permeation in human TPC1 has a positive feedback on channel activity while Na(+) acts as a negative regulator. (PMID:28252105)
• a cluster of arginine residues in the first domain required for selective voltage-gating of TPC1 map not to the voltage-sensing fourth transmembrane region (S4) but to a cytosolic downstream region (S4-S5 linker). (PMID:29129203)
• cryo-EM structure of human TPC2 provides insights into the mechanism of PI(3,5)P2-regulated gating of TPC2, which is distinct from that of TPC1 (PMID:30860481)
• TPC1 is involved in the norepinephrine (NE)-stimulated [Ca(2+)]i rise in Smooth muscle cells. Inhibition of TPC1 activity by NED 19 could be the reason for partial inhibition of aortic rings contraction in response to NE. (PMID:31557916)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpcn1	ENSDARG00000062362
mus_musculus	Tpcn1	ENSMUSG00000032741
rattus_norvegicus	Tpcn1	ENSRNOG00000059344

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), CACNA1I (ENSG00000100346), CACNA1F (ENSG00000102001), NALCN (ENSG00000102452), SCN2A (ENSG00000136531), SCN7A (ENSG00000136546), CACNA1A (ENSG00000141837), SCN1A (ENSG00000144285), CACNA1B (ENSG00000148408), CACNA1C (ENSG00000151067), CATSPER3 (ENSG00000152705), SCN3A (ENSG00000153253), CACNA1D (ENSG00000157388), TPCN2 (ENSG00000162341), CATSPER2 (ENSG00000166762), SCN11A (ENSG00000168356), SCN9A (ENSG00000169432), CATSPER1 (ENSG00000175294), SCN5A (ENSG00000183873), SCN10A (ENSG00000185313), CATSPER4 (ENSG00000188782), CACNA1H (ENSG00000196557), SCN8A (ENSG00000196876), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Two pore channel protein 1 — Q9ULQ1 (reviewed: Q9ULQ1)

Alternative names: Two pore calcium channel protein 1, Voltage-dependent calcium channel protein TPC1

All UniProt accessions (13): Q9ULQ1, B7Z3R2, F8VR74, F8VS97, F8VV93, F8VVY9, F8VZZ6, F8W0K7, F8W0P9, F8W1G4, F8W1L6, H0YHX1, H0YIK4

UniProt curated annotations — full annotation on UniProt →

Function. Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a voltage-gated highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) that senses pH changes and confers electrical excitability to organelles. Localizes to the early and recycling endosomes membranes where it plays a role in the uptake and processing of proteins and regulates organellar membrane excitability, membrane trafficking and pH homeostasis. Ion selectivity is not fixed but rather agonist-dependent and under defined ionic conditions, can be readily activated by both NAADP and PI(3,5)P2. Required for mTOR-dependent nutrient sensing. (Microbial infection) During Ebola virus (EBOV) infection, controls the movement of endosomes containing virus particles and is required by EBOV to escape from the endosomal network into the cell cytoplasm.

Subunit / interactions. Dimer. Interacts with MTOR; the interaction is required for TPCN1 ATP sensitivity. Interacts with STX7, STX8 and STX12. Interacts with JPT2. Found in a complex with LSM12, TPCN1 and TPCN2.

Subcellular location. Lysosome membrane. Endosome membrane. Early endosome membrane. Recycling endosome membrane.

Tissue specificity. Highest expression found in the heart and kidney, and lowest expression found in the spleen.

Post-translational modifications. N-glycosylated.

Activity regulation. Na(+) current is inhibited by ATP in a MTORC-dependent manner. ATP sensitivity is independent of PI(3,5)P2. Probably regulated by Mg(2+) ions, cytosolic Mg(2+) selectively inhibits outward current while lysosomal Mg(2+) modestly inhibits both the outward and inward currents. In the absence of Mg(2+), NAADP readily activates TPCN2, with properties similar to PI(3,5)P2. Both current elicited by PI(3,5)P2 as well as NAADP are inhibited by tetrandrine.

Domain organisation. Each of the two internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments represent the voltage-sensor and are characterized by a series of positively charged amino acids at every third position.

Similarity. Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. Two pore calcium channel subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9ULQ1-1	1	yes
Q9ULQ1-2	2
Q9ULQ1-3	3

RefSeq proteins (5): NP_001137291, NP_001288143, NP_001338275, NP_001338276, NP_060371* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005821	Ion_trans_dom	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR028801	TPC1_animal	Family

Pfam: PF00520

Catalyzed reactions (Rhea), 2 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (47 total): topological domain 15, transmembrane region 12, splice variant 4, mutagenesis site 4, glycosylation site 3, intramembrane region 2, region of interest 2, compositionally biased region 2, chain 1, coiled-coil region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULQ1-F1	85.40	0.61

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 (3): 599, 611, 616

Mutagenesis-validated functional residues (4):

Position	Phenotype
219–223	loss of voltage sensitivity.
273	loss of naadp-mediated cytoplasmic calcium release.
539	loss of voltage sensitivity.
740–741	no effect on subcellular location.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 250 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, MYOGENIN_Q6, GOCC_VACUOLAR_MEMBRANE, LFA1_Q6, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, CTATGCA_MIR153, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, COUP_01, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTERACTION_WITH_HOST, GOBP_VIRAL_LIFE_CYCLE

GO Biological Process (9): positive regulation of autophagy (GO:0010508), monoatomic ion transmembrane transport (GO:0034220), endocytosis involved in viral entry into host cell (GO:0075509), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), calcium-mediated signaling (GO:0019722), sodium ion transmembrane transport (GO:0035725), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (12): voltage-gated sodium channel activity (GO:0005248), ligand-gated sodium channel activity (GO:0015280), syntaxin binding (GO:0019905), voltage-gated channel activity (GO:0022832), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), NAADP-sensitive calcium-release channel activity (GO:0072345), phosphatidylinositol-3,5-bisphosphate binding (GO:0080025), intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity (GO:0097682), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (9): lysosome (GO:0005764), lysosomal membrane (GO:0005765), endosome (GO:0005768), endosome membrane (GO:0010008), early endosome membrane (GO:0031901), monoatomic ion channel complex (GO:0034702), endolysosome (GO:0036019), recycling endosome membrane (GO:0055038), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
monoatomic cation transmembrane transport	2
sodium channel activity	2
ligand-gated monoatomic cation channel activity	2
lysosome	2
endosome	2
endosome membrane	2
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
monoatomic ion transport	1
transmembrane transport	1
symbiont entry into host cell	1
metal ion transport	1
intracellular signaling cassette	1
sodium ion transport	1
cellular process	1
calcium ion transport	1
SNARE binding	1
gated channel activity	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
intracellularly gated calcium channel activity	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
intracellularly ligand-gated monoatomic ion channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
lytic vacuole	1
lytic vacuole membrane	1
endomembrane system	1
cytoplasmic vesicle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
early endosome	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1336 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPCN1	RET	P07949	802
TPCN1	PTCH1	Q13635	764
TPCN1	SLC5A5	Q92911	727
TPCN1	TSHR	P16473	678
TPCN1	TPCN2	Q8NHX9	671
TPCN1	MCOLN1	Q9GZU1	656
TPCN1	TG	P01266	625
TPCN1	CCK	P06307	603
TPCN1	BRAF	P15056	594
TPCN1	RET	P07949	586
TPCN1	MCOLN3	Q8TDD5	546
TPCN1	MCOLN2	Q8IZK6	540
TPCN1	JPT2	Q9H910	512
TPCN1	SLC8B1	Q6J4K2	493
TPCN1	DRC10	Q96DY2	488

IntAct

47 interactions, top by confidence:

A	B	Type	Score
SEC13	SEC16A	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
TPCN1	TPCN2	psi-mi:“MI:0915”(physical association)	0.590
TPCN2	TPCN1	psi-mi:“MI:0915”(physical association)	0.590
TPCN1	TPCN2	psi-mi:“MI:0403”(colocalization)	0.590
TPCN2	TPCN1	psi-mi:“MI:2364”(proximity)	0.590
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TMEM171	THAP12	psi-mi:“MI:0914”(association)	0.530
TMEM171	B3GAT3	psi-mi:“MI:0914”(association)	0.530
TPCN1	HAX1	psi-mi:“MI:0915”(physical association)	0.530
HAX1	TPCN1	psi-mi:“MI:0407”(direct interaction)	0.530
TPCN1	TPCN1	psi-mi:“MI:0915”(physical association)	0.470
TPCN1	TPCN1	psi-mi:“MI:2364”(proximity)	0.470
TPCN1	MTOR	psi-mi:“MI:0915”(physical association)	0.400
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
EFNA4	NBAS	psi-mi:“MI:0914”(association)	0.350

BioGRID (40): TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), TPCN1 (Proximity Label-MS), TPCN1 (Proximity Label-MS), TPCN1 (Proximity Label-MS), TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-RNA), TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS), TPCN1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMD4, B7ZC96, F6RG56, O65718, O73606, P17971, P17972, P70259, P97557, Q00195, Q03041, Q05973, Q0P583, Q16280, Q16281, Q24278, Q28718, Q29441, Q3U2S8, Q3UW12, Q5F4C0, Q5R5V8, Q5RC10, Q60565, Q62398, Q64359, Q6PIU1, Q6Q760, Q6R6I7, Q8AYS8, Q8BWC0, Q8BXR5, Q8BZN2, Q8IV77, Q8IZF0, Q8IZK6, Q8K595, Q8TDD5, Q90980, Q94AS9

Diamond homologs: A2APX8, A2ASI5, B1AWN6, B1AYL1, D0E0C2, F1LQQ7, O08562, O46669, O73705, O73706, O88420, O88457, P02719, P04774, P04775, P08104, P0DMA5, P15389, P15390, P35498, P35499, P35500, Q01118, Q05973, Q14524, Q15858, Q20JQ7, Q28371, Q28644, Q2XVR3, Q2XVR4, Q2XVR5, Q2XVR6, Q2XVR7, Q62205, Q62968, Q6QIY3, Q99250, Q9EQJ0, Q9ER60

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 52 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Asparagine N-linked glycosylation	6	11.3×	1e-03
G alpha (q) signalling events	5	9.0×	8e-03
Membrane Trafficking	7	8.1×	1e-03
Vesicle-mediated transport	7	7.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	92
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

5398 predictions. Top by Δscore:

Variant	Effect	Δscore
12:113226712:A:AG	acceptor_gain	1.0000
12:113226713:A:G	acceptor_gain	1.0000
12:113226719:A:AG	acceptor_gain	1.0000
12:113226720:A:G	acceptor_gain	1.0000
12:113226721:A:G	acceptor_gain	1.0000
12:113226722:C:G	acceptor_gain	1.0000
12:113226727:GAA:G	acceptor_gain	1.0000
12:113226962:AAA:A	donor_gain	1.0000
12:113226963:AA:A	donor_gain	1.0000
12:113226963:AAG:A	donor_loss	1.0000
12:113226964:AGT:A	donor_loss	1.0000
12:113226965:G:GG	donor_gain	1.0000
12:113226966:T:G	donor_loss	1.0000
12:113260361:A:AG	acceptor_gain	1.0000
12:113260364:GCAGA:G	acceptor_loss	1.0000
12:113260365:CAGA:C	acceptor_loss	1.0000
12:113260366:A:AC	acceptor_loss	1.0000
12:113260366:A:AG	acceptor_gain	1.0000
12:113260366:AGAT:A	acceptor_gain	1.0000
12:113260367:G:GG	acceptor_gain	1.0000
12:113260367:GATG:G	acceptor_gain	1.0000
12:113260489:CCAGG:C	donor_loss	1.0000
12:113260490:CAGGT:C	donor_loss	1.0000
12:113260493:G:C	donor_loss	1.0000
12:113260493:G:GG	donor_gain	1.0000
12:113266175:TTCA:T	acceptor_loss	1.0000
12:113266177:CA:C	acceptor_loss	1.0000
12:113266178:A:AT	acceptor_loss	1.0000
12:113266179:G:A	acceptor_loss	1.0000
12:113266179:GGAA:G	acceptor_gain	1.0000

AlphaMissense

5379 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:113273667:T:C	L314P	1.000
12:113290967:T:C	L643P	1.000
12:113290984:T:A	W649R	1.000
12:113290984:T:C	W649R	1.000
12:113266183:G:C	G81R	0.999
12:113266210:C:G	H90D	0.999
12:113267909:T:A	W161R	0.999
12:113267909:T:C	W161R	0.999
12:113268872:G:C	R220P	0.999
12:113269762:T:C	L222P	0.999
12:113269845:G:C	G250R	0.999
12:113273275:T:C	L276P	0.999
12:113273278:T:C	L277P	0.999
12:113273286:G:C	A280P	0.999
12:113273574:C:A	P283Q	0.999
12:113273637:T:C	L304P	0.999
12:113273649:T:C	L308P	0.999
12:113273665:C:A	N313K	0.999
12:113273665:C:G	N313K	0.999
12:113276923:T:C	L316P	0.999
12:113276926:C:A	A317D	0.999
12:113276943:T:C	F323L	0.999
12:113276945:C:A	F323L	0.999
12:113276945:C:G	F323L	0.999
12:113276998:C:A	A341D	0.999
12:113278232:T:A	W410R	0.999
12:113278232:T:C	W410R	0.999
12:113288804:G:C	G585R	0.999
12:113288805:G:A	G585D	0.999
12:113290237:A:C	S636R	0.999

dbSNP variants (sampled 300 via entrez): RS1000006454 (12:113287273 G>A,C), RS1000035243 (12:113264257 G>A,C), RS1000041427 (12:113229460 G>A), RS1000076163 (12:113230384 G>A), RS1000162101 (12:113242084 A>G), RS1000170698 (12:113298814 A>T), RS1000251422 (12:113223148 G>C), RS1000276469 (12:113264548 G>A), RS1000293502 (12:113289360 C>A,T), RS1000300002 (12:113251045 G>A), RS1000326898 (12:113223342 G>A), RS1000416707 (12:113236316 G>A,C), RS1000437079 (12:113250717 G>A), RS1000476379 (12:113222841 C>T), RS1000566700 (12:113254326 A>T)

Disease associations

OMIM: gene MIM:609666 | 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
GCST001738_6	Response to fenofibrate (adiponectin levels)	5.000000e-08

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 — CatSper and Two-Pore channels (TPC)

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
phosphatidyl (3,5) inositol bisphosphate	Activation	6.52	pEC50
verapamil	Inhibition	4.64	pIC50
Cd2+	Inhibition	3.74	pIC50

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, affects methylation, decreases methylation	3
Cisplatin	affects cotreatment, increases expression, decreases expression	3
Tobacco Smoke Pollution	decreases expression, decreases methylation, increases expression	3
bisphenol A	increases expression, affects cotreatment, decreases expression	2
Estradiol	increases expression	2
Nickel	decreases expression	2
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
chloroacetaldehyde	increases expression	1
kojic acid	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	increases expression	1
3-deazaneplanocin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
apicidin	decreases expression	1
entinostat	increases expression	1
abrine	decreases expression	1
mocetinostat	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Vorinostat	increases expression	1
Cidofovir	increases expression	1
Acetaminophen	decreases expression	1

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8CT	Ubigene A-549 TPCN1 KO	Cancer cell line	Male
CVCL_D8XH	Ubigene HCT 116 TPCN1 KO	Cancer cell line	Male
CVCL_D9UP	Ubigene HEK293 TPCN1 KO	Transformed cell line	Female
CVCL_E0RU	Ubigene HeLa TPCN1 KO	Cancer cell line	Female
CVCL_E2MG	HAP1 TPCN1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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