MCOLN3

Summary

MCOLN3 (mucolipin TRP cation channel 3, HGNC:13358) is a protein-coding gene on chromosome 1p22.3, encoding Mucolipin-3 (Q8TDD5). Nonselective cation channel probably playing a role in the regulation of membrane trafficking events.

This gene encodes one of members of the mucolipin cation channel proteins. Mutation studies of the highly similar protein in mice have shown that the protein is found in cochlea hair cells, and mutant mice show early-onset hearing loss and balance problems. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 55283 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 75 total
• Druggable target: yes
• MANE Select transcript: NM_018298

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13358
Approved symbol	MCOLN3
Name	mucolipin TRP cation channel 3
Location	1p22.3
Locus type	gene with protein product
Status	Approved
Aliases	TRPML3, FLJ11006, TRP-ML3
Ensembl gene	ENSG00000055732
Ensembl biotype	protein_coding
OMIM	607400
Entrez	55283

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 20 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000341115, ENST00000370587, ENST00000370589, ENST00000474447, ENST00000475312, ENST00000490600, ENST00000889288, ENST00000889289, ENST00000889290, ENST00000889291, ENST00000911967, ENST00000953532, ENST00000953533, ENST00000953534, ENST00000953535, ENST00000953536, ENST00000953537, ENST00000953538, ENST00000953539, ENST00000953540, ENST00000953541, ENST00000953542, ENST00000953543

RefSeq mRNA: 2 — MANE Select: NM_018298 NM_001253693, NM_018298

CCDS: CCDS58009, CCDS701

Canonical transcript exons

ENST00000370589 — 13 exons

Exon	Start	End
ENSE00000830888	85025939	85026088
ENSE00000956835	85022299	85022400
ENSE00001067255	85045133	85045362
ENSE00001453091	85018082	85019257
ENSE00003459799	85032696	85032792
ENSE00003481826	85021070	85021276
ENSE00003484733	85041010	85041177
ENSE00003528863	85034098	85034251
ENSE00003636964	85026172	85026284
ENSE00003647233	85032872	85032956
ENSE00003665653	85022070	85022192
ENSE00003669991	85029106	85029205
ENSE00003850841	85048396	85048500

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 96.20.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6961 / max 114.2587, expressed in 756 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13016	2.6961	756

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	96.20	gold quality
adrenal cortex	UBERON:0001235	95.69	gold quality
left adrenal gland	UBERON:0001234	95.44	gold quality
left adrenal gland cortex	UBERON:0035825	95.40	gold quality
right adrenal gland	UBERON:0001233	95.39	gold quality
corpus epididymis	UBERON:0004359	93.57	gold quality
germinal epithelium of ovary	UBERON:0001304	92.65	gold quality
pituitary gland	UBERON:0000007	92.35	gold quality
adenohypophysis	UBERON:0002196	92.30	gold quality
adrenal gland	UBERON:0002369	91.35	gold quality
upper leg skin	UBERON:0004262	90.30	gold quality
body of pancreas	UBERON:0001150	89.39	gold quality
skin of hip	UBERON:0001554	86.71	gold quality
right atrium auricular region	UBERON:0006631	86.43	gold quality
cardiac atrium	UBERON:0002081	86.03	gold quality
pancreas	UBERON:0001264	84.95	gold quality
cardiac muscle of right atrium	UBERON:0003379	84.01	gold quality
caput epididymis	UBERON:0004358	83.88	gold quality
visceral pleura	UBERON:0002401	83.86	gold quality
cauda epididymis	UBERON:0004360	83.84	gold quality
calcaneal tendon	UBERON:0003701	83.16	gold quality
metanephros cortex	UBERON:0010533	82.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.46	gold quality
endocervix	UBERON:0000458	81.75	gold quality
right lung	UBERON:0002167	81.66	gold quality
buccal mucosa cell	CL:0002336	81.56	gold quality
islet of Langerhans	UBERON:0000006	81.39	gold quality
upper lobe of left lung	UBERON:0008952	80.26	gold quality
sural nerve	UBERON:0015488	80.17	gold quality
tendon	UBERON:0000043	80.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting MCOLN3, 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-12118	100.00	65.88	1270
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-106A-3P	99.53	67.58	995
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863

Literature-anchored findings (GeneRIF, showing 15)

• 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)
• The A419P mutation affects TRPLMe channel glycosylation and causes massive cell death (PMID:17962195)
• TRPML3(A419P) and (I362T+A419P) at physiological potentials may have a role in hair cell degeneration and deafness (PMID:18162548)
• First characterization of wild-type TRPML3 calcium-permeable channel properties and its regulation by extracytosolic (luminal)hydrogen ion (H+). (PMID:18369318)
• The deaf-waddler isoform of PMCA2, operating at 30% efficacy, showed a significantly decreased ability to rescue the Ca(2+) loading of cells expressing TRPML3(A419P). (PMID:19299509)
• Results show that mucolipin 3 is a novel calcium channel that plays a crucial role in the regulation of cargo trafficking along the endosomal pathway. (PMID:19497048)
• These findings reveal a prominent role for TRPML3 in regulating endocytosis, membrane trafficking and autophagy, perhaps by controlling the Ca(2+) in the vicinity of cellular organelles that is necessary to regulate these cellular events. (PMID:19522758)
• Data show that TRPMLs form distinct functional channel complexes. (PMID:19885840)
• analysis of the TRPML3 channel pore and its stable expansion by the Varitint-Waddler-causing mutation (PMID:20378547)
• TRPML 1, 2 and 3 assemblies regulated cell viability and starvation-induced autophagy. (PMID:20736310)
• Negatively charged amino acids in the extracellular loops of TRPML3 may interfere with the observed sodium inhibition. (PMID:22753890)
• TRPML3 and TRPV5 heteromers could have a biological function (PMID:23469151)
• these results suggest that TRPML3 plays a role in autophagosome maturation through the interaction with GATE16, by providing Ca(2+) in the fusion process. (PMID:24269818)
• The work elucidates the molecular architecture and provides insights into how multiple ligands regulate TRPML1 and TRPML3. (Review) (PMID:29577631)
• palmitoylation is a prerequisite for the function of MCOLN3/TRPML3 as a Ca(2+) channel in autophagosome formation. (PMID:30215288)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcoln3a	ENSDARG00000078363
danio_rerio	MCOLN3	ENSDARG00000102050
mus_musculus	Mcoln3	ENSMUSG00000036853
rattus_norvegicus	Mcoln3	ENSRNOG00000015024
drosophila_melanogaster	CG42638	FBGN0261361
drosophila_melanogaster	Trpml	FBGN0262516
caenorhabditis_elegans		WBGENE00000846

Paralogs (2): MCOLN1 (ENSG00000090674), MCOLN2 (ENSG00000153898)

Protein

Protein identifiers

Mucolipin-3 — Q8TDD5 (reviewed: Q8TDD5)

Alternative names: Transient receptor potential channel mucolipin 3

All UniProt accessions (3): B1ANB7, Q8TDD5, S4R386

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. Mediates release of Ca(2+) from endosomes to the cytoplasm, contributes to endosomal acidification and is involved in the regulation of membrane trafficking and fusion in the endosomal pathway. Also permeable to Mg(2+), Na(+) and K(+). Does not seem to act as mechanosensory transduction channel in inner ear sensory hair cells. Proposed to play a critical role at the cochlear stereocilia ankle-link region during hair-bundle growth. Involved in the regulation of autophagy. Through association with GABARAPL2 may be involved in autophagosome formation possibly providing Ca(2+) for the fusion process. Through a possible and probably tissue-specific heteromerization with MCOLN1 may be at least in part involved in many lysosome-dependent cellular events. Possible heteromeric ion channel assemblies with TRPV5 show pharmacological similarity with TRPML3.

Subunit / interactions. Homotetramer. Can heterooligomerize with MCOLN1; heteromeric assemblies have different channel properties as compared to the respective homooligomers and may be tissue-specific. May heterooligomerize with TRPV5 to form a functional distinct ion channel. Interacts with GABARAPL2.

Subcellular location. Cell membrane. Early endosome membrane. Late endosome membrane. Lysosome membrane. Cytoplasmic vesicle. Autophagosome membrane.

Post-translational modifications. N-glycosylated.

Activity regulation. Channel activity is activated by PtdIns(3,5)P2 (phosphatidylinositol 3,5-bisphosphate). Inhibited by lumenal H(+) and Na(+). The channel pore shows dynamic behavior and undergoes spontaneous, Ca(2+)-dependent modulation when conducting Ca(2+).

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. MCOLN3 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TDD5-1	1	yes
Q8TDD5-2	2

RefSeq proteins (2): NP_001240622, NP_060768* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013122	PKD1_2_channel	Domain
IPR039031	Mucolipin	Family
IPR047317	MCOLN3_ELD	Domain
IPR049134	MCLN_ECD	Domain

Pfam: PF08016, PF21381

Catalyzed reactions (Rhea), 3 shown:

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

UniProt features (42 total): mutagenesis site 15, topological domain 8, transmembrane region 6, glycosylation site 3, region of interest 2, disulfide bond 2, chain 1, intramembrane region 1, short sequence motif 1, site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6AYF	ELECTRON MICROSCOPY	3.62
6AYE	ELECTRON MICROSCOPY	4.06
6AYG	ELECTRON MICROSCOPY	4.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDD5-F1	84.51	0.56

Functional residue map

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

Catalytic / active sites (1): 305 (interaction with phosphoinositides)

Disulfide bonds (2): 159–185, 238–269

Glycosylation sites (3): 138, 172, 205

Mutagenesis-validated functional residues (15):

Position	Phenotype
108	abolishes basal channel activity without affecting channel activation by a synthetic agonist; when associated with n-111
111	abolishes basal channel activity without affecting channel activation by a synthetic agonist; when associated with n-108
112	abolishes basal channel activity without affecting channel activation by a synthetic agonist; when associated with n-108
252	increases inhibition by lumenal h(+). decreases inhibition by lumenal h(+); when associated with a-283.
273	increases inhibition by lumenal h(+). decreases inhibition by lumenal h(+); when associated with a-283.
283	constitutive active channel; abolishes inhibition by lumenal h(+); retains the ca(2+)-dependent inactivation of the ca(2
283	increases inhibition by lumenal h(+).
419	constitutive active channel; abolishes inhibition by lumenal h(+); increases the pore diameter.
423	nearly abolishes channel activation by a synthetic agonist.
449	constitutive active channel; greatly impairs inhibition by lumenal na(+).
449	abolishes channel activity.
458–459	enhances endocytosis.
458	nearly abolishes channel activity; inhibits starvation-induced autophagy.
459	decreases in ca(2+) permeability and selectivity; decreases channel pore dynamic behavior.
497	nearly abolishes channel activation by a synthetic agonist.

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: 198 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOCC_VACUOLAR_MEMBRANE, JAEGER_METASTASIS_DN, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOZGIT_ESR1_TARGETS_DN, GOBP_NEUROGENESIS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_EAR_DEVELOPMENT

GO Biological Process (10): locomotory behavior (GO:0007626), inner ear auditory receptor cell differentiation (GO:0042491), calcium ion transmembrane transport (GO:0070588), monoatomic ion transport (GO:0006811), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220), sodium ion transmembrane transport (GO:0035725), potassium ion transmembrane transport (GO:0071805), monoatomic cation transmembrane transport (GO:0098655), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (7): monoatomic anion channel activity (GO:0005253), calcium channel activity (GO:0005262), potassium channel activity (GO:0005267), sodium channel activity (GO:0005272), lipid binding (GO:0008289), NAADP-sensitive calcium-release channel activity (GO:0072345), monoatomic cation channel activity (GO:0005261)

GO Cellular Component (10): autophagosome membrane (GO:0000421), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

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
monoatomic cation transmembrane transport	3
monoatomic cation channel activity	3
monoatomic ion transmembrane transport	2
monoatomic ion channel activity	2
endosome membrane	2
cellular anatomical structure	2
behavior	1
hair cell differentiation	1
inner ear receptor cell differentiation	1
calcium ion transport	1
transport	1
intracellular signaling cassette	1
monoatomic ion transport	1
transmembrane transport	1
sodium ion transport	1
potassium ion transport	1
monoatomic cation transport	1
monoatomic anion transport	1
monoatomic anion transmembrane transporter activity	1
calcium ion transmembrane transporter activity	1
potassium ion transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
binding	1
intracellularly gated calcium channel activity	1
monoatomic cation transmembrane transporter activity	1
vacuolar membrane	1
autophagosome	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
early endosome	1
late endosome	1
intracellular anatomical structure	1
lytic vacuole	1
endomembrane system	1
cytoplasmic vesicle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

736 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCOLN3	TRPV5	Q9NQA5	915
MCOLN3	MCOLN2	Q8IZK6	716
MCOLN3	FRMD6	Q96NE9	658
MCOLN3	TPCN2	Q8NHX9	630
MCOLN3	TRPA1	O75762	629
MCOLN3	KCNJ10	P78508	617
MCOLN3	PKD2L1	Q9P0L9	609
MCOLN3	TPM3	P06753	601
MCOLN3	CD63	P08962	594
MCOLN3	CD59	P13987	556
MCOLN3	TPCN1	Q9ULQ1	546
MCOLN3	TRPM8	Q7Z2W7	543
MCOLN3	TRPM4	Q8TD43	539
MCOLN3	TRPM7	Q96QT4	536
MCOLN3	TRPC3	Q13507	532

IntAct

13 interactions, top by confidence:

A	B	Type	Score
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
MCOLN2	MCOLN3	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
SRPK2	MCOLN3	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MCOLN3		psi-mi:“MI:0915”(physical association)	0.400
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
CCR6	GPR89A	psi-mi:“MI:0914”(association)	0.350
MCOLN3	ACY3	psi-mi:“MI:0914”(association)	0.350
FLVCR2	PLPP1	psi-mi:“MI:0914”(association)	0.350
MFSD10	NDUFS8	psi-mi:“MI:0914”(association)	0.350
SPNS2	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (146): DCAKD (Affinity Capture-MS), LSR (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), ATP8B2 (Affinity Capture-MS), PGAP1 (Affinity Capture-MS), SLC12A9 (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), DNAJC11 (Affinity Capture-MS), SCAP (Affinity Capture-MS), MFAP3 (Affinity Capture-MS), ATP13A2 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), ABHD16A (Affinity Capture-MS), PIGO (Affinity Capture-MS), SNX14 (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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2341 predictions. Top by Δscore:

Variant	Effect	Δscore
1:85029104:A:AC	donor_gain	1.0000
1:85029105:C:CC	donor_gain	1.0000
1:85032694:A:AC	donor_gain	1.0000
1:85032695:C:CC	donor_gain	1.0000
1:85032695:CAGT:C	donor_gain	1.0000
1:85032793:C:CC	acceptor_gain	1.0000
1:85032953:CACT:C	acceptor_gain	1.0000
1:85032955:CT:C	acceptor_gain	1.0000
1:85032962:A:C	acceptor_gain	1.0000
1:85034259:C:CT	acceptor_gain	1.0000
1:85041175:CAGCT:C	acceptor_gain	1.0000
1:85045249:T:C	donor_gain	1.0000
1:85045358:CATCT:C	acceptor_gain	1.0000
1:85045361:CT:C	acceptor_gain	1.0000
1:85045363:C:CC	acceptor_gain	1.0000
1:85045363:C:CG	acceptor_loss	1.0000
1:85045364:T:A	acceptor_loss	1.0000
1:85019255:TTG:T	acceptor_gain	0.9900
1:85022399:CT:C	acceptor_gain	0.9900
1:85025943:G:C	donor_gain	0.9900
1:85026285:C:CC	acceptor_gain	0.9900
1:85029099:CACT:C	donor_loss	0.9900
1:85029100:ACTT:A	donor_loss	0.9900
1:85029101:CT:C	donor_loss	0.9900
1:85029102:TTAC:T	donor_loss	0.9900
1:85029103:TA:T	donor_loss	0.9900
1:85029104:AC:A	donor_loss	0.9900
1:85029105:C:CA	donor_loss	0.9900
1:85029203:TATC:T	acceptor_loss	0.9900
1:85029204:ATC:A	acceptor_loss	0.9900

AlphaMissense

3710 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:85021112:A:C	S495R	0.998
1:85021112:A:T	S495R	0.998
1:85021114:T:G	S495R	0.998
1:85021136:G:C	S487R	0.998
1:85021136:G:T	S487R	0.998
1:85021138:T:G	S487R	0.998
1:85021227:C:A	G457V	0.997
1:85021227:C:T	G457E	0.997
1:85021229:A:C	N456K	0.997
1:85021229:A:T	N456K	0.997
1:85021236:A:G	L454P	0.997
1:85021274:A:C	F441L	0.997
1:85021274:A:T	F441L	0.997
1:85021276:A:G	F441L	0.997
1:85022145:G:C	F415L	0.997
1:85022145:G:T	F415L	0.997
1:85022147:A:G	F415L	0.997
1:85022343:A:G	W385R	0.997
1:85022343:A:T	W385R	0.997
1:85021110:A:G	L496P	0.996
1:85021225:C:G	D458H	0.996
1:85021245:A:G	L451P	0.996
1:85022099:A:G	W431R	0.996
1:85022099:A:T	W431R	0.996
1:85025990:A:C	S348R	0.996
1:85025990:A:T	S348R	0.996
1:85025992:T:G	S348R	0.996
1:85021142:G:C	F485L	0.995
1:85021142:G:T	F485L	0.995
1:85021144:A:G	F485L	0.995

dbSNP variants (sampled 300 via entrez): RS1000164194 (1:85025384 TGGG>T,TGG), RS1000225711 (1:85035321 C>T), RS1000271034 (1:85017618 A>G), RS1000460804 (1:85042687 T>C), RS1000572675 (1:85036953 A>G), RS1000709629 (1:85044543 C>T), RS1000812068 (1:85042249 G>C), RS1000815609 (1:85037292 T>C), RS1000838974 (1:85023056 G>A), RS1000840357 (1:85023383 G>A), RS1000959381 (1:85029988 G>A), RS1001229490 (1:85025085 T>C), RS1001294672 (1:85031520 T>A), RS1001464946 (1:85030277 T>C), RS1001534097 (1:85040709 G>T)

Disease associations

OMIM: gene MIM:607400 | 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): CHEMBL1293243 (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 (10 total), top 10:

Ligand	Action	Affinity	Parameter
SF-11	Activation	6.59	pEC50
SF-21	Activation	6.35	pEC50
SN-1	Activation	6.06	pEC50
SN-2	Activation	5.96	pEC50
ML3-SA1	Activation	5.05	pEC50
PRU-12	Inhibition	4.85	pIC50
PRU-10	Inhibition	4.8	pIC50
estradiol 3-methyl ether	Inhibition	4.71	pIC50
Gd3+	Antagonist	4.7	pIC50
EVP-21	Activator	4.28	pEC50

ChEMBL bioactivities

169 potent at pChembl≥5 of 198 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.60	EC50	252.6	nM	CHEMBL548708
6.54	EC50	292	nM	CHEMBL1377193
6.49	EC50	325	nM	CHEMBL548708
6.47	EC50	342	nM	CHEMBL3191441
6.43	EC50	370	nM	CHEMBL1422566
6.35	EC50	450	nM	CHEMBL1521361
6.23	EC50	590	nM	CHEMBL584031
6.21	EC50	620	nM	CHEMBL1377681
6.11	EC50	781	nM	CHEMBL1339229
6.09	EC50	819	nM	CHEMBL1369781
6.08	EC50	823	nM	CHEMBL1521361
6.06	EC50	872	nM	CHEMBL1377681
6.02	EC50	950	nM	CHEMBL1492498
6.00	EC50	1005	nM	CHEMBL1369781
5.99	EC50	1030	nM	CHEMBL1414923
5.99	EC50	1030	nM	CHEMBL1492498
5.96	EC50	1090	nM	CHEMBL1380043
5.95	EC50	1120	nM	CHEMBL1569585
5.95	EC50	1124	nM	CHEMBL1370397
5.94	EC50	1160	nM	CHEMBL1479781
5.94	EC50	1160	nM	CHEMBL1405843
5.94	EC50	1160	nM	CHEMBL1472570
5.91	EC50	1240	nM	CHEMBL1472554
5.88	EC50	1330	nM	CHEMBL1306290
5.88	EC50	1330	nM	CHEMBL1370397
5.87	EC50	1360	nM	CHEMBL1380043
5.86	EC50	1370	nM	CHEMBL1378564
5.84	EC50	1430	nM	CHEMBL1437613
5.84	EC50	1430	nM	CHEMBL1446118
5.84	EC50	1450	nM	CHEMBL1470726
5.82	EC50	1520	nM	CHEMBL1534146
5.80	EC50	1590	nM	CHEMBL1382128
5.80	EC50	1600	nM	CHEMBL1309129
5.78	EC50	1670	nM	CHEMBL1489784
5.77	EC50	1710	nM	CHEMBL1428855
5.75	EC50	1798	nM	CHEMBL1437613
5.75	EC50	1780	nM	CHEMBL1517137
5.75	EC50	1770	nM	CHEMBL1540621
5.75	EC50	1770	nM	CHEMBL1430530
5.74	EC50	1840	nM	CHEMBL1479177
5.74	EC50	1830	nM	CHEMBL1333562
5.74	EC50	1840	nM	CHEMBL1560703
5.74	EC50	1810	nM	CHEMBL1465176
5.74	EC50	1820	nM	CHEMBL1573517
5.73	EC50	1870	nM	CHEMBL1523363
5.72	EC50	1900	nM	CHEMBL1352344
5.72	EC50	1900	nM	CHEMBL1408062
5.70	EC50	2000	nM	CHEMBL1446118
5.69	EC50	2060	nM	CHEMBL1504000
5.69	EC50	2060	nM	CHEMBL1444583

PubChem BioAssay actives

5 with measured affinity, of 42 total; 5 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
N-[(1S,2S)-2-[4-(2-phenylethyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760515: Activation of human TRPML3-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	5.4000	uM
N-[(1S,2S)-2-[4-[(4-methylphenyl)methyl]piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760515: Activation of human TRPML3-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	5.8000	uM
N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]-4-methylbenzenesulfonamide	1760515: Activation of human TRPML3-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	8.5000	uM
N-[(1S,2S)-2-(4-phenylpiperazin-1-yl)cyclohexyl]benzenesulfonamide	1760515: Activation of human TRPML3-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	9.5000	uM
N-[(1S,2S)-2-(3,4-dihydro-1H-isoquinolin-2-yl)cyclohexyl]benzenesulfonamide	1760515: Activation of human TRPML3-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	9.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	8
sodium arsenite	decreases expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Arsenic Trioxide	increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases 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	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Cisplatin	decreases expression	1
Cytarabine	decreases expression	1
Doxorubicin	increases expression	1
Lead	decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 5 binding, 3 functional, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613957	Functional	PUBCHEM_BIOASSAY: Late stage results from the probe development effort to identify selective agonists of the Transient Receptor Potential Channels 3 (TRPML3): fluorescence-based cell-based dose response assay for TRPML3 agonists. (Class of	PubChem BioAssay data set
CHEMBL1737899	Unclassified	PUBCHEM_BIOASSAY: Late stage results from the probe development efforts to identify agonists of the Transient Receptor Potential Channels 3 and 2 (TRPML3 and TRPML2). (Class of assay: screening) [Related pubchem assays (depositor defined):A	PubChem BioAssay data set
CHEMBL4819508	Binding	Activation of human TRPML3-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

7 cell lines: 5 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7UY	Ubigene A-549 MCOLN3 KO	Cancer cell line	Male
CVCL_D8QH	Ubigene HCT 116 MCOLN3 KO	Cancer cell line	Male
CVCL_D9K2	Ubigene HEK293 MCOLN3 KO	Transformed cell line	Female
CVCL_E0HR	Ubigene HeLa MCOLN3 KO	Cancer cell line	Female
CVCL_E6IB	HEK293 TRPML3-YFP	Transformed cell line	Female
CVCL_SX65	HAP1 MCOLN3 (-) 1	Cancer cell line	Male
CVCL_XQ33	HAP1 MCOLN3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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