TPCN2

Summary

TPCN2 (two pore segment channel 2, HGNC:20820) is a protein-coding gene on chromosome 11q13.3, encoding Two pore channel protein 2 (Q8NHX9). Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate).

This gene encodes a putative cation-selective ion channel with two repeats of a six-transmembrane-domain. The protein localizes to lysosomal membranes and enables nicotinic acid adenine dinucleotide phosphate (NAADP) -induced calcium ion release from lysosome-related stores. This ubiquitously expressed gene has elevated expression in liver and kidney. Two common nonsynonymous SNPs in this gene strongly associate with blond versus brown hair pigmentation.

Source: NCBI Gene 219931 — RefSeq curated summary.

At a glance

• Gene–disease (curated): albinism (Limited, GenCC)
• GWAS associations: 31
• Clinical variants (ClinVar): 173 total — 1 likely-pathogenic
• MANE Select transcript: NM_139075

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20820
Approved symbol	TPCN2
Name	two pore segment channel 2
Location	11q13.3
Locus type	gene with protein product
Status	Approved
Aliases	TPC2
Ensembl gene	ENSG00000162341
Ensembl biotype	protein_coding
OMIM	612163
Entrez	219931

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 19 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000294309, ENST00000442692, ENST00000534832, ENST00000535009, ENST00000542467, ENST00000635811, ENST00000637342, ENST00000637504, ENST00000897238, ENST00000897239, ENST00000897240, ENST00000897241, ENST00000897242, ENST00000897243, ENST00000897244, ENST00000897245, ENST00000897246, ENST00000897247, ENST00000915419, ENST00000915420, ENST00000915421, ENST00000915422, ENST00000915423

RefSeq mRNA: 1 — MANE Select: NM_139075 NM_139075

CCDS: CCDS8189

Canonical transcript exons

ENST00000294309 — 25 exons

Exon	Start	End
ENSE00001630452	69087875	69090597
ENSE00001753410	69055175	69055352
ENSE00002501398	69054721	69054797
ENSE00003477100	69067503	69067605
ENSE00003479921	69070430	69070495
ENSE00003486447	69063895	69063967
ENSE00003487639	69071923	69072023
ENSE00003490248	69062884	69062990
ENSE00003499116	69057578	69057694
ENSE00003562413	69071356	69071420
ENSE00003606742	69072627	69072708
ENSE00003672478	69054033	69054097
ENSE00003799742	69048932	69049106
ENSE00003852354	69081400	69081499
ENSE00003855214	69083945	69084016
ENSE00003855511	69078734	69078793
ENSE00003856466	69079834	69079883
ENSE00003857448	69086523	69086604
ENSE00003858542	69078892	69079020
ENSE00003861932	69085671	69085752
ENSE00003862198	69087112	69087206
ENSE00003868964	69085848	69085930
ENSE00003871136	69078482	69078601
ENSE00003879132	69072915	69073001
ENSE00003879920	69085210	69085286

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 90.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.6574 / max 401.6199, expressed in 1806 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115564	12.1113	1798
115563	1.8514	826
115562	0.3665	157
115566	0.2740	111
115565	0.0542	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	90.03	gold quality
kidney epithelium	UBERON:0004819	89.17	silver quality
ileal mucosa	UBERON:0000331	88.12	gold quality
mucosa of stomach	UBERON:0001199	87.87	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.43	gold quality
lower esophagus	UBERON:0013473	87.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.93	gold quality
body of uterus	UBERON:0009853	85.48	gold quality
monocyte	CL:0000576	85.27	gold quality
leukocyte	CL:0000738	84.95	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.72	gold quality
left uterine tube	UBERON:0001303	84.18	gold quality
tibialis anterior	UBERON:0001385	84.18	silver quality
right lobe of liver	UBERON:0001114	84.15	gold quality
blood	UBERON:0000178	84.03	gold quality
cerebellar hemisphere	UBERON:0002245	83.81	gold quality
granulocyte	CL:0000094	83.80	gold quality
cerebellar cortex	UBERON:0002129	83.60	gold quality
epithelial cell of pancreas	CL:0000083	83.53	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.46	gold quality
cerebellum	UBERON:0002037	83.37	gold quality
cortex of kidney	UBERON:0001225	83.35	gold quality
left ovary	UBERON:0002119	83.05	gold quality
left ventricle myocardium	UBERON:0006566	82.82	gold quality
endocervix	UBERON:0000458	82.81	gold quality
popliteal artery	UBERON:0002250	82.69	gold quality
tibial artery	UBERON:0007610	82.68	gold quality
ectocervix	UBERON:0012249	82.43	gold quality
esophagus	UBERON:0001043	82.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

56 targeting TPCN2, 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-3646	100.00	73.56	5283
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-508-5P	99.41	64.25	1248

Literature-anchored findings (GeneRIF, showing 27)

• Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair. (PMID:18488028)
• analysis of two-pore channel 2 (TPCN2)-mediated Ca2+ currents in isolated lysosomes (PMID:20495006)
• TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+. (PMID:20720007)
• These results provide strong evidence for modulation of store-operated Ca(2+) entry by TPC2 involving de novo association between TPC2 and STIM1, as well as Orai1, in human cells. (PMID:23077736)
• Notably, NAADP-mediated Ca(2+) release in intact cells is regulated by Mg(2+), PI(3,5)P2, and P38/JNK kinases, thus paralleling regulation of TPC2 currents. (PMID:24502975)
• TPC2, but not TPC1, caused a proliferation of endolysosomal structures, dysregulating intracellular trafficking, and cellular pigmentation. (PMID:25157141)
• SNPs within Tpcn2 are associated with fasting insulin in humans. (PMID:25236446)
• These results demonstrate that a VEGFR2/NAADP/TPC2/Ca(2+) signaling pathway is critical for VEGF-induced angiogenesis (PMID:25331892)
• TPC2 is thus a potential drug target within a pathogenic LRRK2 cascade that disrupts Ca(2+)-dependent trafficking in Parkinson disease (PMID:25416817)
• 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)
• 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)
• Results show that PDGs use previously unknown mechanisms of membrane dynamics and content exchange that are regulated by TPC2. (PMID:26202466)
• Here, using live cell imaging, the authors obtained evidence that in contrast to the new model, ebolavirus enters cells through endolysosomes that contain both NPC1 and TPC2. (PMID:26468524)
• Results demonstrated the unique bell-shaped regulation of hTPC2 channel activity by [NAADP] and that channel activity is modulated by PKA phosphorylation at position S666. (PMID:26838264)
• rs1551305 single nucleotide polymorphism is associated with type 2 diabetes risk. (PMID:26918892)
• TPC2 regulates pigmentation through two fundamental determinants of melanosome function: pH and size. (PMID:27140606)
• These findings indicate potential differential regulation of signaling processes by TPC1 and TPC2 in breast cancer cells. (PMID:27353380)
• the divergent pore regions from human TPC2, a two-domain channel that holds a key intermediate position in the evolution of voltage-gated ion channels, were characterized. (PMID:27941820)
• The ion selectivity of Arabidopsis thaliana TPC1 was compared with the selectivity of human TPC2. HsTPC2 was confirmed as a Na(+)-selective channel activated by phosphatidylinositol 3,5-bisphosphate. The ion permeability ratios of HsTPC2 and its mutants were calculated. (PMID:28096396)
• TPC2 polymorphisms are associated with a hair pigmentation. (PMID:28923947)
• Data (including data from studies using tissue from knockout mice) suggest that beta-adrenergic stimulation of pancreas leads to glucagon secretion by hierarchy of calcium signaling in glucagon-secreting cell; such signaling is initiated by cAMP-induced TPC2-dependent calcium release from acidic stores and is further amplified by calcium release from endoplasmic reticulum. (PMID:29563152)
• PI(3,5)P2-binding site in hTPC2 identified at positively charged amino acids (K203, K204, and K207) in the linker between transmembrane helices S4 and S5 and by S322 in the cytosolic extension of S6 and protein-lipid interface upon mutations of residues within the lipid-binding pocket had neither an effect on the binding behavior nor on the channel’s lipid sensitivity. (PMID:29705952)
• support a role of TPC2 in autophagy progression and extracellular vesicle trafficking in cancer cells (PMID:29990474)
• 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)
• Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect. (PMID:33465068)
• Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2. (PMID:33875769)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpcn2	ENSDARG00000100420
mus_musculus	Tpcn2	ENSMUSG00000048677
rattus_norvegicus	Tpcn2	ENSRNOG00000013387

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), CATSPER2 (ENSG00000166762), SCN11A (ENSG00000168356), SCN9A (ENSG00000169432), CATSPER1 (ENSG00000175294), SCN5A (ENSG00000183873), SCN10A (ENSG00000185313), TPCN1 (ENSG00000186815), CATSPER4 (ENSG00000188782), CACNA1H (ENSG00000196557), SCN8A (ENSG00000196876), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Two pore channel protein 2 — Q8NHX9 (reviewed: Q8NHX9)

Alternative names: Two pore calcium channel protein 2

All UniProt accessions (4): A0A1B0GTM1, A0A1B0GUM5, E7ETX0, Q8NHX9

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 highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate). Localizes to the lysosomal and late endosome membranes where it regulates organellar membrane excitability, membrane trafficking, and pH homeostasis. Is associated with a plethora of physiological processes, including mTOR-dependent nutrient sensing, skin pigmentation and autophagy. 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. As calcium channel, it increases the pH in the lysosomal lumen, as sodium channel, it promotes lysosomal exocytosis. Plays a crucial role in endolysosomal trafficking in the endolysosomal degradation pathway and is potentially involved in the homeostatic control of many macromolecules and cell metabolites. Also expressed in melanosomes of pigmented cells where mediates a Ca(2+) channel and/or PI(3,5)P2-activated melanosomal Na(+) channel to acidify pH and inhibit tyrosinase activity required for melanogenesis and pigmentation. Unlike the voltage-dependent TPCN1, TPCN2 is voltage independent and can be activated solely by PI(3,5)P2 binding. In contrast, PI(4,5)P2, PI(3,4)P2, PI(3)P and PI(5)P have no obvious effect on channel activation. (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. (Microbial infection) Required for cell entry of coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus EMC (HCoV-EMC), by endocytosis.

Subunit / interactions. Homodimer. Interacts with LRRK2. Interacts with HAX1. Interacts with MTOR; the interaction is required for TPCN2 ATP sensitivity. Found in a complex with LSM12, TPCN1 and TPCN2. Interacts with LSM12.

Subcellular location. Late endosome membrane. Lysosome membrane. Melanosome membrane.

Tissue specificity. Widely expressed. Expressed at high level in liver and kidney.

Post-translational modifications. N-glycosylated.

Activity regulation. 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. Na(+) current is inhibited by ATP in a MTORC-dependent manner. ATP sensitivity is independent of 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 probably represent the voltage-sensor and are characterized by a series of positively charged amino acids at every third position.

Polymorphism. Genetic variants in TPCN2 define the skin/hair/eye pigmentation variation locus 10 (SHEP10) [MIM:612267]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.

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

RefSeq proteins (1): NP_620714* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005821	Ion_trans_dom	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR028798	TPC2	Family

Pfam: PF00520

Catalyzed reactions (Rhea), 2 shown:

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

UniProt features (89 total): helix 35, topological domain 15, transmembrane region 12, mutagenesis site 9, turn 5, sequence variant 4, strand 3, intramembrane region 2, glycosylation site 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8OUO	ELECTRON MICROSCOPY	3
6NQ2	ELECTRON MICROSCOPY	3.4
6NQ1	ELECTRON MICROSCOPY	3.5
6NQ0	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHX9-F1	80.49	0.36

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): 611, 618

Mutagenesis-validated functional residues (9):

Position	Phenotype
11–12	localizes at the plasma membrane.
203	strongly reduces binding with phosphatidylinositol 3,5-bisphosphate.
204	strongly reduces binding with phosphatidylinositol 3,5-bisphosphate. decreases sodium transport. no effect on calcium re
207	reduces binding with phosphatidylinositol 3,5-bisphosphate.
265	no effect on lysosomal location. loss of naadp-sensitive calcium-release channel activity. inhibits ebola virus infectio
276	not activated by phosphatidylinositol 3,5-bisphosphate.
322	reduces binding with phosphatidylinositol 3,5-bisphosphate.
329	reduces binding with phosphatidylinositol 3,5-bisphosphate.
551	requires both phosphatidylinositol 3,5-bisphosphate and a positive membrane potential for activation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 188 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_LYSOSOMAL_TRANSPORT, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, chr11q13, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT

GO Biological Process (19): intracellular calcium ion homeostasis (GO:0006874), smooth muscle contraction (GO:0006939), lysosome organization (GO:0007040), regulation of autophagy (GO:0010506), regulation of exocytosis (GO:0017157), receptor-mediated endocytosis of virus by host cell (GO:0019065), calcium-mediated signaling (GO:0019722), response to vitamin D (GO:0033280), monoatomic ion transmembrane transport (GO:0034220), sodium ion transmembrane transport (GO:0035725), negative regulation of developmental pigmentation (GO:0048086), release of sequestered calcium ion into cytosol (GO:0051209), intracellular pH reduction (GO:0051452), endocytosis involved in viral entry into host cell (GO:0075509), endosome to lysosome transport of low-density lipoprotein particle (GO:0090117), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (11): voltage-gated calcium channel activity (GO:0005245), calcium channel activity (GO:0005262), ligand-gated sodium channel activity (GO:0015280), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), 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), protein binding (GO:0005515), voltage-gated channel activity (GO:0022832)

GO Cellular Component (10): lysosome (GO:0005764), lysosomal membrane (GO:0005765), cytosol (GO:0005829), endosome membrane (GO:0010008), late endosome membrane (GO:0031902), melanosome membrane (GO:0033162), monoatomic ion channel complex (GO:0034702), endolysosome membrane (GO:0036020), endosome (GO:0005768), 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
symbiont entry into host cell	2
monoatomic cation transmembrane transport	2
transport	2
ligand-gated monoatomic cation channel activity	2
cellular anatomical structure	2
endosome membrane	2
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
muscle contraction	1
lytic vacuole organization	1
autophagy	1
regulation of catabolic process	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
receptor-mediated endocytosis	1
endocytosis involved in viral entry into host cell	1
intracellular signaling cassette	1
response to vitamin	1
response to lipid	1
response to oxygen-containing compound	1
monoatomic ion transport	1
transmembrane transport	1
sodium ion transport	1
developmental pigmentation	1
regulation of developmental pigmentation	1
negative regulation of biological process	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
regulation of intracellular pH	1
endosome to lysosome transport	1
vesicle-mediated cholesterol transport	1
metal ion transport	1
cellular process	1
calcium ion transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
sodium channel activity	1

Protein interactions and networks

STRING

1300 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPCN2	SLC24A4	Q8NFF2	914
TPCN2	SLC24A5	Q71RS6	903
TPCN2	SLC45A2	Q9UMX9	799
TPCN2	OCA2	Q04671	786
TPCN2	MCOLN1	Q9GZU1	762
TPCN2	MC1R	Q01726	689
TPCN2	ASIP	P42127	685
TPCN2	TYRP1	P17643	673
TPCN2	TPCN1	Q9ULQ1	671
TPCN2	PIKFYVE	Q9Y2I7	662
TPCN2	MCOLN2	Q8IZK6	659
TPCN2	TRPC1	P48995	657
TPCN2	TYR	P14679	649
TPCN2	MCOLN3	Q8TDD5	630
TPCN2	IRF4	Q15306	618

IntAct

30 interactions, top by confidence:

A	B	Type	Score
PTPRA	LGALS1	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
HAX1	TPCN2	psi-mi:“MI:0915”(physical association)	0.590
TPCN2	HAX1	psi-mi:“MI:0407”(direct interaction)	0.590
TPCN2	AP3B1	psi-mi:“MI:0914”(association)	0.530
TPCN2	TPCN2	psi-mi:“MI:0915”(physical association)	0.470
TPCN2	TPCN2	psi-mi:“MI:2364”(proximity)	0.470
TPCN2	MTOR	psi-mi:“MI:0915”(physical association)	0.400
TPCN2	ADRA1A	psi-mi:“MI:0915”(physical association)	0.370
TPCN2	DDX11L8	psi-mi:“MI:0914”(association)	0.350
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
OR10H2	ABCD4	psi-mi:“MI:0914”(association)	0.350
TMEM154	VPS26A	psi-mi:“MI:0914”(association)	0.350
TMEM154	RPSA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (106): ANKRD27 (Affinity Capture-MS), AGBL5 (Affinity Capture-MS), USP32 (Affinity Capture-MS), DENND6A (Affinity Capture-MS), TRAPPC8 (Affinity Capture-MS), WDR44 (Affinity Capture-MS), TPCN2 (Affinity Capture-MS), CLCN3 (Affinity Capture-MS), FBXO10 (Affinity Capture-MS), ARRB2 (Affinity Capture-MS), RRAGB (Affinity Capture-MS), PI4K2A (Affinity Capture-MS), RELT (Affinity Capture-MS), AP3B1 (Affinity Capture-MS), WDR11 (Affinity Capture-MS)

ESM2 similar proteins: A2AIR5, A5PK40, A6NFX1, B9EKX1, D2HKB0, D3ZG27, F1NCD6, O60242, P23979, P46098, P62955, P62956, P62957, Q08DW9, Q0VBU9, Q13635, Q14B62, Q3T9X0, Q4R766, Q504N2, Q5H8A4, Q5RB09, Q5RIV7, Q5T4D3, Q5VTY9, Q5VYX0, Q5VZY2, Q5ZIN0, Q61115, Q66H95, Q6AYT7, Q6ZW05, Q80ZF8, Q8BG19, Q8BWB6, Q8IZD6, Q8N2K0, Q8N6M3, Q8NEB5, Q8NHX9

Diamond homologs: A0JMD4, Q8BWC0, Q8NHX9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	118
Likely benign	10
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3377525	NM_139075.4(TPCN2):c.628C>T (p.Arg210Cys)	Likely pathogenic

SpliceAI

5742 predictions. Top by Δscore:

Variant	Effect	Δscore
11:69054093:TTCAG:T	donor_loss	1.0000
11:69054094:TCAGG:T	donor_loss	1.0000
11:69054095:CAGGT:C	donor_loss	1.0000
11:69054097:GG:G	donor_loss	1.0000
11:69054098:GTC:G	donor_loss	1.0000
11:69054099:T:A	donor_loss	1.0000
11:69054719:A:AG	acceptor_gain	1.0000
11:69054720:G:GA	acceptor_gain	1.0000
11:69054720:GTACC:G	acceptor_gain	1.0000
11:69055210:T:TA	acceptor_gain	1.0000
11:69055220:C:A	acceptor_gain	1.0000
11:69055351:AGGT:A	donor_loss	1.0000
11:69055352:GG:G	donor_loss	1.0000
11:69055353:G:T	donor_loss	1.0000
11:69057572:TTGCA:T	acceptor_loss	1.0000
11:69057573:TGCA:T	acceptor_loss	1.0000
11:69057575:CAG:C	acceptor_loss	1.0000
11:69057576:AG:A	acceptor_gain	1.0000
11:69057577:G:GC	acceptor_loss	1.0000
11:69057577:GG:G	acceptor_gain	1.0000
11:69057690:ATGAG:A	donor_loss	1.0000
11:69057691:TGAGG:T	donor_loss	1.0000
11:69057694:GGTA:G	donor_loss	1.0000
11:69057695:GT:G	donor_loss	1.0000
11:69057696:T:A	donor_loss	1.0000
11:69070425:TTTA:T	acceptor_loss	1.0000
11:69070428:A:AG	acceptor_gain	1.0000
11:69070428:A:C	acceptor_loss	1.0000
11:69070428:AGT:A	acceptor_gain	1.0000
11:69070429:G:GA	acceptor_gain	1.0000

AlphaMissense

4872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:69086548:T:A	W677R	0.997
11:69086548:T:C	W677R	0.997
11:69086551:T:A	W678R	0.995
11:69086551:T:C	W678R	0.995
11:69071403:T:C	F315L	0.994
11:69071405:C:A	F315L	0.994
11:69071405:C:G	F315L	0.994
11:69054086:G:C	D55H	0.993
11:69071377:T:C	L306P	0.993
11:69085890:T:A	W655R	0.993
11:69085890:T:C	W655R	0.993
11:69086582:T:C	L688P	0.993
11:69067579:T:C	L268P	0.992
11:69067582:T:C	L269P	0.992
11:69085237:G:T	G597W	0.992
11:69085866:T:A	W647R	0.992
11:69085866:T:C	W647R	0.992
11:69085738:T:C	F636L	0.991
11:69085740:C:A	F636L	0.991
11:69085740:C:G	F636L	0.991
11:69054089:G:C	A56P	0.990
11:69085739:T:G	F636C	0.990
11:69054725:G:C	R60P	0.989
11:69062912:C:G	P192R	0.989
11:69067570:T:C	L265P	0.989
11:69070495:G:A	G299R	0.989
11:69070495:G:C	G299R	0.989
11:69085864:T:C	L646P	0.989
11:69085886:C:A	N653K	0.989
11:69085886:C:G	N653K	0.989

dbSNP variants (sampled 300 via entrez): RS1000066459 (11:69059823 C>T), RS1000092536 (11:69084478 C>A,T), RS1000192593 (11:69082324 A>C,G), RS1000271432 (11:69047679 G>C), RS1000283158 (11:69079894 G>A), RS1000287030 (11:69050821 G>C,T), RS1000407567 (11:69060668 C>T), RS1000526478 (11:69084615 C>T), RS1000544750 (11:69063451 C>G), RS1000876537 (11:69048940 G>A,T), RS1001001466 (11:69053388 C>T), RS1001053627 (11:69053572 G>A), RS1001071599 (11:69075796 G>T), RS1001180809 (11:69067425 G>A,T), RS1001255896 (11:69089465 C>T)

Disease associations

OMIM: gene MIM:612163 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
albinism	Limited	Autosomal dominant

Mondo (1): albinism (MONDO:0043209)

Orphanet (0):

HPO phenotypes

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

GWAS associations

31 associations (top):

Study	Trait	p-value
GCST000194_1	Blond vs. brown hair color	4.000000e-30
GCST002936_21	Cadmium levels	7.000000e-07
GCST003021_3	Brown vs. non-brown hair color	1.000000e-11
GCST003022_3	Light vs. dark hair color	3.000000e-13
GCST003023_2	Blond vs non-blond hair color	3.000000e-14
GCST003061_13	Cutaneous malignant melanoma	3.000000e-07
GCST005897_40	Low tan response	1.000000e-29
GCST006075_12	Hair color	1.000000e-100
GCST006288_185	Heel bone mineral density	2.000000e-09
GCST006288_424	Heel bone mineral density	6.000000e-13
GCST006288_45	Heel bone mineral density	5.000000e-21
GCST006979_409	Heel bone mineral density	8.000000e-62
GCST006988_166	Blond vs. brown/black hair color	5.000000e-188
GCST006988_176	Blond vs. brown/black hair color	2.000000e-308
GCST006989_33	Brown vs. black hair color	6.000000e-48
GCST006989_34	Brown vs. black hair color	1.000000e-32
GCST007505_22	Nevus count or cutaneous melanoma	1.000000e-06
GCST007515_34	Type 2 diabetes	5.000000e-07
GCST007516_14	Type 2 diabetes (adjusted for BMI)	2.000000e-08
GCST007517_17	Type 2 diabetes	2.000000e-06
GCST007518_22	Type 2 diabetes (adjusted for BMI)	2.000000e-06
GCST007876_117	Estimated glomerular filtration rate	3.000000e-10
GCST008058_242	Estimated glomerular filtration rate	1.000000e-13
GCST010797_15	Breast cancer, ovarian cancer or prostate cancer (pleiotropy)	1.000000e-09
GCST011956_126	Systemic lupus erythematosus	6.000000e-13
GCST012227_673	Hip circumference adjusted for BMI	1.000000e-08
GCST90020026_509	Hip index	3.000000e-09
GCST90020026_510	Hip index	4.000000e-09
GCST90020028_2003	Hip circumference adjusted for BMI	3.000000e-08
GCST90020028_2004	Hip circumference adjusted for BMI	2.000000e-14

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color
EFO:0004279	suntan
EFO:0009270	heel bone mineral density
EFO:0004632	nevus count
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000417	Albinism	C11.270.040; C16.320.290.040; C16.320.565.100.102; C16.320.850.080; C17.800.621.440.102; C17.800.827.080; C18.452.648.100.102

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 (8 total), top 8:

Ligand	Action	Affinity	Parameter
phosphatidyl (3,5) inositol bisphosphate	Activation	6.4	pEC50
SG-005	Inhibition	5.6	pIC50
MT-8	Inhibition	5.59	pIC50
TPC2-A1-N	Activation	5.11	pEC50
SG-094	Inhibition	5.08	pIC50
UM-9	Inhibition	5.02	pIC50
verapamil	Inhibition	5.0	pIC50
TPC2-A1-P	Activation	4.98	pEC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	6
Arsenic	affects cotreatment, decreases expression, increases abundance, affects methylation	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance	2
entinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression, increases methylation	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzene	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Demecolcine	increases expression	1
Ethinyl Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	decreases methylation	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vincristine	increases expression	1
Cyclosporine	decreases methylation	1

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8CU	Ubigene A-549 TPCN2 KO	Cancer cell line	Male
CVCL_D8XI	Ubigene HCT 116 TPCN2 KO	Cancer cell line	Male
CVCL_D9UQ	Ubigene HEK293 TPCN2 KO	Transformed cell line	Female
CVCL_E0RV	Ubigene HeLa TPCN2 KO	Cancer cell line	Female
CVCL_E0WM	Ubigene Jurkat, Clone E6-1 TPCN2 KO	Cancer cell line	Male
CVCL_E1CK	Ubigene T98G TPCN2 KO	Cancer cell line	Male
CVCL_E2MH	HAP1 TPCN2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001596	PHASE2	COMPLETED	Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome
NCT01176435	PHASE2	COMPLETED	Trial of L-DOPA as a Treatment to Improve Vision in Albinism
NCT01663935	PHASE2	TERMINATED	Vision Response to Dopamine Replacement
NCT01838655	PHASE1/PHASE2	COMPLETED	Nitisinone for Type 1B Oculocutaneous Albinism
NCT00001153	Not specified	COMPLETED	Visual Function and Ocular Pigmentation in Albinism
NCT04281732	Not specified	UNKNOWN	Visual Performance Measures in a Virtual Reality Environment for Assessing Clinical Trial Outcomes in Those With Severely Reduced Vision
NCT04658381	Not specified	COMPLETED	Genetic Analysis and Multimodal Retinal Imaging of Asymptomatic Fovea Plana Cases in the General Population
NCT05696912	Not specified	UNKNOWN	Functional Tests to Resolve Unsolved Rare Diseases. Rares.
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT06491615	Not specified	RECRUITING	National Ophthalmic Genotyping and Phenotyping Network (eyeGENE (Registered Trademark)), Stage 3 - Expansion of DNA and Data Repositories for Rare Inherited Ophthalmic Diseases
NCT07400913	Not specified	NOT_YET_RECRUITING	Implementation of Long-read Sequencing for the Diagnosis of Rare Diseases.