MCOLN2

Summary

MCOLN2 (mucolipin TRP cation channel 2, HGNC:13357) is a protein-coding gene on chromosome 1p22.3, encoding Mucolipin-2 (Q8IZK6). Nonselective cation channel probably playing a role in the regulation of membrane trafficking events.

Mucolipins constitute a family of cation channel proteins with homology to the transient receptor potential superfamily. In mammals, the mucolipin family includes 3 members, MCOLN1 (MIM 605248), MCOLN2, and MCOLN3 (MIM 607400), that exhibit a common 6-membrane-spanning topology. Homologs of mammalian mucolipins exist in Drosophila and C. elegans. Mutations in the human MCOLN1 gene cause mucolipodosis IV (MIM 262650) (Karacsonyi et al., 2007 [PubMed 17662026]).

Source: NCBI Gene 255231 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 102 total
• Druggable target: yes
• MANE Select transcript: NM_153259

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13357
Approved symbol	MCOLN2
Name	mucolipin TRP cation channel 2
Location	1p22.3
Locus type	gene with protein product
Status	Approved
Aliases	TRPML2, FLJ36691, TRP-ML2
Ensembl gene	ENSG00000153898
Ensembl biotype	protein_coding
OMIM	607399
Entrez	255231

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000284027, ENST00000370608, ENST00000463065, ENST00000530971, ENST00000531325, ENST00000531874, ENST00000945492, ENST00000945493, ENST00000945494, ENST00000945495, ENST00000945496, ENST00000945497

RefSeq mRNA: 2 — MANE Select: NM_153259 NM_001330647, NM_153259

CCDS: CCDS30762, CCDS81347

Canonical transcript exons

ENST00000370608 — 14 exons

Exon	Start	End
ENSE00001230738	84925583	84926721
ENSE00003470153	84965549	84965708
ENSE00003474717	84952243	84952339
ENSE00003506368	84929558	84929679
ENSE00003520165	84947033	84947132
ENSE00003537082	84952446	84952530
ENSE00003540289	84940879	84940991
ENSE00003555892	84931362	84931568
ENSE00003595839	84956431	84956584
ENSE00003599443	84937981	84938082
ENSE00003615940	84939553	84939702
ENSE00003639450	84996796	84997113
ENSE00003645564	84958529	84958702
ENSE00003673599	84937755	84937877

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 94.66.

FANTOM5 (CAGE): breadth broad, TPM avg 12.4914 / max 931.5368, expressed in 651 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13014	11.3605	590
13015	0.6900	254
13013	0.4389	156
13012	0.0020	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	94.66	gold quality
cartilage tissue	UBERON:0002418	93.06	gold quality
rectum	UBERON:0001052	91.20	gold quality
mucosa of transverse colon	UBERON:0004991	90.95	gold quality
lymph node	UBERON:0000029	87.54	gold quality
right adrenal gland cortex	UBERON:0035827	87.42	gold quality
ileal mucosa	UBERON:0000331	86.85	gold quality
granulocyte	CL:0000094	86.46	gold quality
left adrenal gland	UBERON:0001234	86.29	gold quality
secondary oocyte	CL:0000655	86.22	gold quality
right adrenal gland	UBERON:0001233	85.80	gold quality
left adrenal gland cortex	UBERON:0035825	85.59	gold quality
adrenal cortex	UBERON:0001235	85.32	gold quality
spleen	UBERON:0002106	85.04	gold quality
oocyte	CL:0000023	84.17	gold quality
right uterine tube	UBERON:0001302	83.94	gold quality
colonic mucosa	UBERON:0000317	83.41	gold quality
adrenal gland	UBERON:0002369	83.16	gold quality
transverse colon	UBERON:0001157	82.93	gold quality
germinal epithelium of ovary	UBERON:0001304	82.55	gold quality
mucosa of sigmoid colon	UBERON:0004993	82.43	gold quality
upper lobe of left lung	UBERON:0008952	82.10	gold quality
vermiform appendix	UBERON:0001154	81.84	gold quality
right lung	UBERON:0002167	81.42	gold quality
epithelium of nasopharynx	UBERON:0001951	80.91	gold quality
upper lobe of lung	UBERON:0008948	80.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.15	gold quality
tonsil	UBERON:0002372	78.78	gold quality
buccal mucosa cell	CL:0002336	78.68	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	597.19
E-ANND-3	yes	4.44
E-MTAB-6379	no	392.25
E-MTAB-7303	no	13.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting MCOLN2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-3606-3P	99.11	69.84	3254

Literature-anchored findings (GeneRIF, showing 13)

• there is a hierarchy controlling the subcellular distributions of the TRPMLs such that TRPML1 and TRPML2 dictate the localization of TRPML3 and not vice versa (PMID:16606612)
• MCOLN2 traffics through the ADP-ribosylation factor 6 (Arf6)-associated pathway, colocalizing with major histocompatibility protein class I and CD59 in long recycling endosomes. (PMID:17662026)
• TRPML1 appears to play a novel role in the tissue-specific transcriptional regulation of TRPML2. (PMID:19763610)
• Data show that TRPMLs form distinct functional channel complexes. (PMID:19885840)
• constitutively active h-TRPML2 leads to cell death by causing Ca(2+) overload (PMID:19940139)
• TRPML 1, 2 and 3 assemblies regulated cell viability and starvation-induced autophagy. (PMID:20736310)
• TRPML2 is activated by lowering the extracellular sodium concentration as well as by a subset of small chemical compounds that were previously identified as activators of TRPML3. (PMID:22753890)
• MCOLN2 is transcriptionally activated by PAX5 and has roles in B cell development and function (PMID:25445271)
• High TRPML-2 expression in glioma cells resulted in increased survival and proliferation signaling, suggesting a pro-tumorigenic role played by TRPML-2 in glioma progression. (PMID:27248469)
• The authors show that MCOLN2 specifically promotes viral vesicular trafficking and subsequent escape from endosomal compartments. This mechanism requires channel activity, occurs independently of antiviral signaling, and broadly applies to enveloped RNA viruses that require transport to late endosomes for infection, including influenza A virus, yellow fever virus, and Zika virus. (PMID:29382735)
• The acidic TRPML2 extracytosolic/lumenal domain (ELD) pre-pore loop exhibits a pH-dependent Ca2+ interaction, suggesting a mechanism for channel activity regulation in the endolysosomal system. (PMID:31178222)
• Endolysosomal ion channel MCOLN2 (Mucolipin-2) promotes prostate cancer progression via IL-1beta/NF-kappaB pathway. (PMID:34548638)
• Functional In Vitro Assessment of VEGFA/NOTCH2 Signaling Pathway and pRB Proteasomal Degradation and the Clinical Relevance of Mucolipin TRPML2 Overexpression in Glioblastoma Patients. (PMID:35054871)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcoln2	ENSDARG00000098918
mus_musculus	Mcoln2	ENSMUSG00000011008
rattus_norvegicus	Mcoln2	ENSRNOG00000015089
drosophila_melanogaster	CG42638	FBGN0261361
drosophila_melanogaster	Trpml	FBGN0262516
caenorhabditis_elegans		WBGENE00000846

Paralogs (2): MCOLN3 (ENSG00000055732), MCOLN1 (ENSG00000090674)

Protein

Protein identifiers

Mucolipin-2 — Q8IZK6 (reviewed: Q8IZK6)

Alternative names: Transient receptor potential channel mucolipin 2

All UniProt accessions (2): Q8IZK6, G5EA24

UniProt curated annotations — full annotation on UniProt →

Function. Nonselective cation channel probably playing a role in the regulation of membrane trafficking events. Acts as a Ca(2+)-permeable cation channel with inwardly rectifying activity. May activate ARF6 and be involved in the trafficking of GPI-anchored cargo proteins to the cell surface via the ARF6-regulated recycling pathway. May play a role in immune processes. In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells. In the innate immune response, may play a role in the regulation of chemokine secretion and macrophage migration. Through a possible and probably tissue-specific heteromerization with MCOLN1 may be at least in part involved in many lysosome-dependent cellular events. Also functions as a Fe(2+) permeable channel.

Subunit / interactions. Forms homooligomeric complexes; probably tetrameric. Can heterooligomerize with MCOLN1; heteromeric assemblies have different channel properties as compared to the respective homooligomers and may be tissue-specific. Interacts with TMEM176A.

Subcellular location. Cell membrane. Late endosome membrane. Lysosome membrane. Recycling endosome membrane.

Activity regulation. Channel activity is reduced by low extracellular/lumenal pH level.

Domain organisation. The most N-terminal extracellular/lumenal domain (referred to as I-II linker or polycystin-mucolipin domain) contributes to a structure with a four-fold rotational symmetry in a tetrameric assembly; the structure contains a central highly electronegative pore with a 14 A diameter. The pore is critical for Ca(2+) and pH regulation. The protruding structure formed by the I-II linkers may contain all the interaction sites with lipids and proteins in the endolysosomal lumen.

Similarity. Belongs to the transient receptor (TC 1.A.4) family. Polycystin subfamily. MCOLN2 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IZK6-1	1	yes
Q8IZK6-2	2

RefSeq proteins (2): NP_001317576, NP_694991* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013122	PKD1_2_channel	Domain
IPR039031	Mucolipin	Family
IPR049134	MCLN_ECD	Domain

Pfam: PF08016, PF21381

Catalyzed reactions (Rhea), 2 shown:

• Fe(2+)(in) = Fe(2+)(out) (RHEA:28486)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (43 total): topological domain 8, strand 8, helix 7, transmembrane region 6, mutagenesis site 3, disulfide bond 2, sequence variant 2, turn 2, chain 1, intramembrane region 1, region of interest 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6HRR	X-RAY DIFFRACTION	2
9EL0	ELECTRON MICROSCOPY	2.45
9EKX	ELECTRON MICROSCOPY	2.6
9EKZ	ELECTRON MICROSCOPY	2.61
9EL1	ELECTRON MICROSCOPY	2.61
9EKY	ELECTRON MICROSCOPY	2.67
6HRS	X-RAY DIFFRACTION	2.95
9EKW	ELECTRON MICROSCOPY	3.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZK6-F1	81.96	0.47

Functional residue map

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

Disulfide bonds (2): 164–190, 243–274

Mutagenesis-validated functional residues (3):

Position	Phenotype
424	constitutive active ca(2+) permeable and inward rectifying channel.
457	does not effect current amplitude; possible effect on regulation.
463–464	blocks channel activity. decreases recycling of internalized cd59 to the cell surface.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3295583	TRP channels
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 280 (showing top): GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOCC_VACUOLAR_MEMBRANE, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOLDRATH_IMMUNE_MEMORY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_IRON_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_LEUKOCYTE_MIGRATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, FOSTER_TOLERANT_MACROPHAGE_DN, GOBP_CYTOKINE_PRODUCTION, GOBP_GRANULOCYTE_MIGRATION, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_10D_UP, GOBP_POSITIVE_REGULATION_OF_CHEMOKINE_PRODUCTION, GOBP_ADAPTIVE_IMMUNE_RESPONSE

GO Biological Process (19): adaptive immune response (GO:0002250), protein transport (GO:0015031), innate immune response (GO:0045087), calcium ion transmembrane transport (GO:0070588), positive regulation of monocyte chemotactic protein-1 production (GO:0071639), positive regulation of macrophage inflammatory protein 1 alpha production (GO:0071642), positive regulation of chemokine (C-C motif) ligand 5 production (GO:0071651), macrophage migration (GO:1905517), neutrophil migration (GO:1990266), positive regulation of chemokine (C-X-C motif) ligand 2 production (GO:2000343), immune system process (GO:0002376), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), calcium-mediated signaling (GO:0019722), positive regulation of chemokine production (GO:0032722), monoatomic ion transmembrane transport (GO:0034220), iron ion transmembrane transport (GO:0034755), monoatomic cation transmembrane transport (GO:0098655), regulation of chemokine (C-X-C motif) ligand 2 production (GO:2000341)

GO Molecular Function (5): calcium channel activity (GO:0005262), iron ion transmembrane transporter activity (GO:0005381), identical protein binding (GO:0042802), NAADP-sensitive calcium-release channel activity (GO:0072345), monoatomic cation channel activity (GO:0005261)

GO Cellular Component (7): plasma membrane (GO:0005886), membrane (GO:0016020), late endosome membrane (GO:0031902), recycling endosome membrane (GO:0055038), lysosome (GO:0005764), endosome (GO:0005768), recycling endosome (GO:0055037)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Stimuli-sensing channels	1
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of chemokine production	4
immune response	2
transport	2
monoatomic cation transmembrane transport	2
chemokine (C-X-C motif) ligand 2 production	2
regulation of chemokine production	2
endosome membrane	2
intracellular protein localization	1
establishment of protein localization	1
defense response to symbiont	1
calcium ion transport	1
monocyte chemotactic protein-1 production	1
regulation of monocyte chemotactic protein-1 production	1
macrophage inflammatory protein-1 alpha production	1
regulation of macrophage inflammatory protein 1 alpha production	1
chemokine (C-C motif) ligand 5 production	1
regulation of chemokine (C-C motif) ligand 5 production	1
mononuclear cell migration	1
myeloid leukocyte migration	1
granulocyte migration	1
regulation of chemokine (C-X-C motif) ligand 2 production	1
biological_process	1
metal ion transport	1
intracellular signaling cassette	1
positive regulation of cytokine production	1
chemokine production	1
monoatomic ion transport	1
transmembrane transport	1
iron ion transport	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
iron ion transmembrane transport	1
transition metal ion transmembrane transporter activity	1
protein binding	1
intracellularly gated calcium channel activity	1
monoatomic ion channel activity	1
monoatomic cation transmembrane transporter activity	1
membrane	1

Protein interactions and networks

STRING

716 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCOLN2	MCOLN3	Q8TDD5	716
MCOLN2	ARF6	P26438	674
MCOLN2	CD59	P13987	672
MCOLN2	TPCN2	Q8NHX9	659
MCOLN2	FRMD6	Q96NE9	649
MCOLN2	TRPC1	P48995	628
MCOLN2	CD63	P08962	615
MCOLN2	TRPA1	O75762	574
MCOLN2	MCOLN1	Q9GZU1	569
MCOLN2	TRPM7	Q96QT4	562
MCOLN2	RAB5A	P20339	550
MCOLN2	TPCN1	Q9ULQ1	540
MCOLN2	TRPV5	Q9NQA5	529
MCOLN2	TRPV2	Q9Y5S1	529
MCOLN2	TRPM3	Q9HCF6	513

IntAct

15 interactions, top by confidence:

A	B	Type	Score
MCOLN1	MCOLN2	psi-mi:“MI:0914”(association)	0.530
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
MCOLN2	MCOLN3	psi-mi:“MI:0914”(association)	0.530
MCOLN2	POTEF	psi-mi:“MI:0914”(association)	0.350
CLEC2B	DEGS1	psi-mi:“MI:0914”(association)	0.350
LY6D	GRIN2A	psi-mi:“MI:0914”(association)	0.350
MFSD10	NDUFS8	psi-mi:“MI:0914”(association)	0.350
MFSD12	SNAP23	psi-mi:“MI:0914”(association)	0.350
SLC16A10	STXBP3	psi-mi:“MI:0914”(association)	0.350
SLC30A5	NBAS	psi-mi:“MI:0914”(association)	0.350
SLC31A1	DENND11	psi-mi:“MI:0914”(association)	0.350
SLC35B2	NDUFS8	psi-mi:“MI:0914”(association)	0.350
SLC9B2	EIF3D	psi-mi:“MI:0914”(association)	0.350
INSR	UBXN8	psi-mi:“MI:0914”(association)	0.350

BioGRID (44): MCOLN2 (Affinity Capture-MS), MCOLN2 (Affinity Capture-MS), MCOLN2 (Synthetic Lethality), MCOLN2 (Affinity Capture-MS), MCOLN2 (Affinity Capture-MS), MCOLN2 (Affinity Capture-MS), MCOLN2 (Affinity Capture-MS), LETMD1 (Affinity Capture-MS), MGAT1 (Affinity Capture-MS), GOLIM4 (Affinity Capture-MS), SOGA3 (Affinity Capture-MS), RAB9A (Affinity Capture-MS), SRC (Affinity Capture-MS), STX16 (Affinity Capture-MS), PDF (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: F6RG56, Q60HE8, Q8IZK6, Q8K595, Q8R4F0, Q8TDD5, Q99J21, Q9GZU1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	6
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

3001 predictions. Top by Δscore:

Variant	Effect	Δscore
1:84939682:C:CT	acceptor_gain	1.0000
1:84947031:A:AC	donor_gain	1.0000
1:84947032:C:CC	donor_gain	1.0000
1:84947032:CTAG:C	donor_gain	1.0000
1:84947158:T:TC	acceptor_gain	1.0000
1:84952441:TTTAC:T	donor_loss	1.0000
1:84952442:TTACC:T	donor_loss	1.0000
1:84952443:TACC:T	donor_loss	1.0000
1:84952444:A:AC	donor_gain	1.0000
1:84952444:A:T	donor_loss	1.0000
1:84952445:C:CG	donor_gain	1.0000
1:84952526:ACAAT:A	acceptor_gain	1.0000
1:84952527:CAAT:C	acceptor_gain	1.0000
1:84952527:CAATC:C	acceptor_gain	1.0000
1:84952528:AAT:A	acceptor_gain	1.0000
1:84952529:AT:A	acceptor_gain	1.0000
1:84952530:TC:T	acceptor_loss	1.0000
1:84952531:C:CC	acceptor_gain	1.0000
1:84952532:T:G	acceptor_loss	1.0000
1:84952537:CAA:C	acceptor_gain	1.0000
1:84952538:A:T	acceptor_gain	1.0000
1:84952539:A:AC	acceptor_gain	1.0000
1:84952539:A:C	acceptor_gain	1.0000
1:84958699:CAAG:C	acceptor_gain	1.0000
1:84958701:AGC:A	acceptor_loss	1.0000
1:84958703:C:CC	acceptor_gain	1.0000
1:84958703:C:T	acceptor_loss	1.0000
1:84958704:T:C	acceptor_loss	1.0000
1:84927086:AATG:A	donor_gain	0.9900
1:84929682:T:C	acceptor_gain	0.9900

AlphaMissense

3780 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:84931428:G:C	S492R	0.998
1:84931428:G:T	S492R	0.998
1:84931430:T:G	S492R	0.998
1:84931404:A:C	S500R	0.997
1:84931404:A:T	S500R	0.997
1:84931406:T:G	S500R	0.997
1:84931528:A:G	L459P	0.997
1:84937784:A:G	W436R	0.997
1:84937784:A:T	W436R	0.997
1:84937786:C:T	G435D	0.997
1:84937830:A:C	F420L	0.997
1:84937830:A:T	F420L	0.997
1:84937832:A:G	F420L	0.997
1:84931434:G:C	F490L	0.996
1:84931434:G:T	F490L	0.996
1:84931436:A:G	F490L	0.996
1:84931516:T:A	D463V	0.996
1:84931517:C:G	D463H	0.996
1:84931519:C:A	G462V	0.996
1:84931521:G:C	N461K	0.996
1:84931521:G:T	N461K	0.996
1:84931566:A:C	F446L	0.996
1:84931566:A:T	F446L	0.996
1:84931568:A:G	F446L	0.996
1:84931402:A:G	L501P	0.995
1:84931537:A:G	L456P	0.995
1:84937777:A:T	V438D	0.995
1:84931516:T:G	D463A	0.994
1:84931519:C:T	G462D	0.994
1:84931533:A:C	F457L	0.994

dbSNP variants (sampled 300 via entrez): RS1000087110 (1:84967229 C>A), RS1000149965 (1:84925255 C>A,G,T), RS1000186344 (1:84966073 T>A,G), RS1000230652 (1:84933358 A>C,G), RS1000236428 (1:84990868 G>A,C), RS1000240495 (1:84933601 G>A), RS1000252177 (1:84975172 C>G,T), RS1000294293 (1:84961098 T>C), RS1000305267 (1:84942105 T>G), RS1000347511 (1:84975457 G>A,C,T), RS1000353347 (1:84968848 C>G), RS1000403285 (1:84954340 C>T), RS1000410095 (1:84927302 C>T), RS1000419098 (1:84997118 C>A,T), RS1000503397 (1:84949465 C>T)

Disease associations

OMIM: gene MIM:607399 | 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
GCST003723_4	Serum sulfate level	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007864	sulfate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879493 (SINGLE PROTEIN)

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 (4 total), top 4:

Ligand	Action	Affinity	Parameter
PRU-12	Inhibition	5.28	pIC50
PRU-10	Inhibition	5.27	pIC50
estradiol 3-methyl ether	Inhibition	5.23	pIC50
ML2-SA1	Agonist	1.24	pEC50

ChEMBL bioactivities

27 potent at pChembl≥5 of 33 total, top 27 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.57	EC50	270	nM	CHEMBL5419687
6.32	EC50	481	nM	CHEMBL5428833
6.17	EC50	675	nM	CHEMBL5432101
6.05	EC50	885	nM	CHEMBL5419801
5.98	EC50	1040	nM	CHEMBL5415308
5.97	EC50	1070	nM	CHEMBL5432025
5.96	EC50	1100	nM	CHEMBL4875551
5.85	EC50	1410	nM	CHEMBL5418881
5.81	EC50	1560	nM	CHEMBL5395068
5.73	EC50	1870	nM	CHEMBL5414380
5.68	EC50	2110	nM	CHEMBL5396548
5.64	IC50	2300	nM	CHEMBL4856175
5.57	EC50	2700	nM	CHEMBL4851704
5.48	EC50	3300	nM	CHEMBL4856175
5.46	EC50	3480	nM	CHEMBL5440855
5.44	EC50	3600	nM	CHEMBL4849322
5.44	EC50	3600	nM	CHEMBL4856363
5.43	EC50	3700	nM	CHEMBL4874310
5.41	EC50	3900	nM	CHEMBL4855589
5.40	EC50	4000	nM	CHEMBL4857820
5.36	EC50	4400	nM	CHEMBL4870275
5.26	IC50	5500	nM	CHEMBL4851134
5.20	EC50	6300	nM	CHEMBL4847300
5.19	EC50	6500	nM	CHEMBL5440040
5.05	EC50	9000	nM	CHEMBL5412687
5.04	EC50	9100	nM	CHEMBL4855846
5.03	EC50	9400	nM	CHEMBL4877013

PubChem BioAssay actives

27 with measured affinity, of 60 total; 26 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(11Z)-2-[4-(3-chlorophenyl)piperazin-1-yl]-4,5,6,7-tetrazatricyclo[11.4.0.03,7]heptadeca-1(17),3,5,11,13,15-hexaene	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	0.2700	uM
1-(3-chlorophenyl)-4-[(R)-(2-fluorophenyl)-(1-propan-2-yltetrazol-5-yl)methyl]piperazine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	0.4810	uM
1-(3-chlorophenyl)-4-[(2-fluorophenyl)-(1-propan-2-yltetrazol-5-yl)methyl]piperazine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	0.6750	uM
1-N-(3-chloro-2-piperidin-1-ylphenyl)-4-N,4-N-dimethylbenzene-1,4-disulfonamide	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	0.8850	uM
2-[4-(3-chlorophenyl)piperazin-1-yl]-4,5,6,7-tetrazatricyclo[10.4.0.03,7]hexadeca-1(16),3,5,12,14-pentaene	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	1.0400	uM
4-(3-chlorophenyl)-1-[(2-fluorophenyl)-(1-propan-2-yltetrazol-5-yl)methyl]piperidine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	1.0700	uM
N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]phenyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	1.1000	uM
2-[4-(3-chlorophenyl)piperazin-1-yl]-4,5,6,7-tetrazatricyclo[11.4.0.03,7]heptadeca-1(17),3,5,13,15-pentaene	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	1.4100	uM
1-(3-chlorophenyl)-4-[(S)-(2-fluorophenyl)-(1-propan-2-yltetrazol-5-yl)methyl]piperazine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	1.5600	uM
1-phenyl-4-[phenyl-(1-propan-2-yltetrazol-5-yl)methyl]piperazine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	1.8700	uM
1-[(2-fluorophenyl)-(1-propan-2-yltetrazol-5-yl)methyl]-4-phenylpiperazine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	2.1100	uM
N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760511: Inhibition of human TRPML2-YFP expressed in HEK293 cells preincubated for 10 mins followed by stimulation with ML-SA1 and measured after 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ic50	2.3000	uM
N-[(1R,2R)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	2.7000	uM
1-(3-chlorophenyl)-4-[(1-ethyltetrazol-5-yl)-(2-fluorophenyl)methyl]piperazine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	3.4800	uM
N-[(1S,2S)-2-[4-(2-phenylethyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	3.6000	uM
N-[(1S,2S)-2-(4-phenylpiperazin-1-yl)cyclohexyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	3.6000	uM
N-[(1S,2S)-2-(4-phenylpiperidin-1-yl)cyclohexyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	3.7000	uM
N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperidin-1-yl]cyclohexyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	3.9000	uM
N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]-4-methylbenzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	4.0000	uM
N-[(1S,2S)-2-[4-[(4-methylphenyl)methyl]piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	4.4000	uM
N-[(1S,2S)-2-(3,4-dihydro-1H-isoquinolin-2-yl)cyclohexyl]benzenesulfonamide	1760511: Inhibition of human TRPML2-YFP expressed in HEK293 cells preincubated for 10 mins followed by stimulation with ML-SA1 and measured after 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ic50	5.5000	uM
N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]thiophene-2-sulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	6.3000	uM
1-(3-chlorophenyl)-4-[(2-fluorophenyl)-(1-propan-2-yltetrazol-5-yl)methyl]piperidine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	6.5000	uM
1-(3-chlorophenyl)-N-(2-fluorophenyl)-N-(1-propan-2-yltetrazol-5-yl)piperidin-4-amine	2005574: Agonist activity at human TRPML1 expressed in HEK293 cells incubated for 1 hr by FLIPR assay	ec50	9.0000	uM
N-[(1S,2S)-2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	9.1000	uM
N-[(1S,2R)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760514: Activation of human TRPML2-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	9.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cisplatin	affects expression, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	decreases methylation	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
monomethylpropion	increases expression	1
chromium hexavalent ion	affects expression	1
abrine	decreases expression	1
gardiquimod	increases expression, decreases reaction	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Clodronic Acid	decreases expression	1
Dieldrin	affects response to substance	1
Estradiol	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	decreases expression	1
Oxygen	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vanadates	decreases expression	1
Vincristine	increases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4819505	Binding	Activation of human TRPML2-YFP expressed in HEK293 cells at 10 uM incubated for 200 secs with compound and measured by Fura-2AM dye based single cell Calcium imaging assay	Chemical and pharmacological characterization of the TRPML calcium channel blockers ML-SI1 and ML-SI3. — Eur J Med Chem

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_D1I0	HAP1 MCOLN2 (-) 1	Cancer cell line	Male
CVCL_D1I1	HAP1 MCOLN2 (-) 2	Cancer cell line	Male
CVCL_D7UX	Ubigene A-549 MCOLN2 KO	Cancer cell line	Male
CVCL_D8QG	Ubigene HCT 116 MCOLN2 KO	Cancer cell line	Male
CVCL_D9K1	Ubigene HEK293 MCOLN2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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