MCOLN1

Summary

MCOLN1 (mucolipin TRP cation channel 1, HGNC:13356) is a protein-coding gene on chromosome 19p13.2, encoding Mucolipin-1 (Q9GZU1). Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis.

This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV.

Source: NCBI Gene 57192 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mucolipidosis type IV (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 23
• Clinical variants (ClinVar): 975 total — 50 pathogenic, 56 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes
• MANE Select transcript: NM_020533

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13356
Approved symbol	MCOLN1
Name	mucolipin TRP cation channel 1
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	TRPML1, ML4, MLIV, MST080, MSTP080, TRPM-L1
Ensembl gene	ENSG00000090674
Ensembl biotype	protein_coding
OMIM	605248
Entrez	57192

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 14 protein_coding, 7 retained_intron

ENST00000264079, ENST00000394321, ENST00000594692, ENST00000595860, ENST00000596008, ENST00000596390, ENST00000598406, ENST00000599334, ENST00000601003, ENST00000602227, ENST00000852000, ENST00000852001, ENST00000852002, ENST00000852003, ENST00000852004, ENST00000852005, ENST00000852006, ENST00000915842, ENST00000915843, ENST00000915844, ENST00000948925

RefSeq mRNA: 1 — MANE Select: NM_020533 NM_020533

CCDS: CCDS12180

Canonical transcript exons

ENST00000264079 — 14 exons

Exon	Start	End
ENSE00000671104	7527520	7527628
ENSE00001053226	7533759	7534009
ENSE00001360743	7527864	7527960
ENSE00003096720	7522624	7522781
ENSE00003460685	7533523	7533653
ENSE00003486821	7528158	7528257
ENSE00003547928	7524961	7525166
ENSE00003567367	7529101	7529202
ENSE00003569622	7528597	7528703
ENSE00003578168	7530286	7530501
ENSE00003583115	7526761	7526926
ENSE00003605338	7526439	7526606
ENSE00003608819	7529590	7529712
ENSE00003655363	7528821	7528970

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 96.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.9611 / max 322.8231, expressed in 1809 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173559	17.5359	1809
173560	4.4252	1247

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	96.35	gold quality
right adrenal gland cortex	UBERON:0035827	95.33	gold quality
right adrenal gland	UBERON:0001233	94.84	gold quality
left adrenal gland	UBERON:0001234	94.58	gold quality
left adrenal gland cortex	UBERON:0035825	94.42	gold quality
adrenal cortex	UBERON:0001235	94.25	gold quality
pituitary gland	UBERON:0000007	93.34	gold quality
stromal cell of endometrium	CL:0002255	93.07	gold quality
adenohypophysis	UBERON:0002196	92.62	gold quality
adrenal gland	UBERON:0002369	92.49	gold quality
granulocyte	CL:0000094	92.10	gold quality
right lung	UBERON:0002167	92.05	gold quality
upper lobe of left lung	UBERON:0008952	91.79	gold quality
mucosa of stomach	UBERON:0001199	91.36	gold quality
omental fat pad	UBERON:0010414	90.92	gold quality
upper lobe of lung	UBERON:0008948	90.91	gold quality
peritoneum	UBERON:0002358	90.87	gold quality
monocyte	CL:0000576	90.61	gold quality
prefrontal cortex	UBERON:0000451	90.57	gold quality
skin of leg	UBERON:0001511	90.36	gold quality
blood	UBERON:0000178	90.26	gold quality
right frontal lobe	UBERON:0002810	90.16	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.05	gold quality
mononuclear cell	CL:0000842	90.04	gold quality
leukocyte	CL:0000738	89.76	gold quality
metanephros cortex	UBERON:0010533	89.73	gold quality
skin of abdomen	UBERON:0001416	89.67	gold quality
apex of heart	UBERON:0002098	89.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.45	gold quality
lower esophagus mucosa	UBERON:0035834	89.44	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.70
E-CURD-112	yes	13.53
E-MTAB-6678	yes	10.84
E-MTAB-6386	no	152.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting MCOLN1, 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-5692A	100.00	74.40	6850
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-3178	89.40	60.05	100

Literature-anchored findings (GeneRIF, showing 40)

• Carrier screening for mucolipidosis type IV in the American Ashkenazi Jewish population from New York metropolitan area (PMID:11845410)
• Review of mutations in MCOLN1 that lead to Mucolipidosis Type IV (PMID:12125810)
• Characterization of the conductance properties of mucolipin-1 in the presence of cations. (PMID:12459486)
• Transfected into Caenorhabditis elegans affects lysosome biogenesis. (PMID:15070744)
• A review of mucolipin-1’s role in calcium signaling and membrane trafficking in mucolipidosis IV. (PMID:15336987)
• ML1 may help regulate vesicular membrane potential, the process of acidification associated with normal vesicular function, and/or Ca2+ transport, into intracellular organelles. (PMID:16133264)
• TRP-ML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage (PMID:16257972)
• TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity (PMID:16361256)
• posttranslational processing of ML1 is more complex than previously described and this protein is delivered to lysosomes primarily via an AP-1-dependent route that does not involve passage via the cell surface (PMID:16517607)
• 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)
• Data demonstrate that the correct localization of mucolipin-1 and the integrity of its ion pore are essential for its physiological function in the late endocytic pathway. (PMID:16978393)
• Sequencing of the MCOLN1 gene identified compound heterozygosity for D362Y and A–>T transition leading to the creation of a novel donor splicing site and a 4-bp deletion from exon 13 at the mRNA level. (PMID:17239335)
• Mutations in the gene coding for TRPML1 result in a lysosomal storage disorder (LSD). (PMID:17306511)
• tTwo PKA (protein kinase A) consensus motifs in the C-terminal tail of MCOLN1, containing Ser(557) and Ser(559). Ser(557) are the principal phosphorylation sites. (PMID:17988215)
• Effects of TRP-ML1 loss on hydrolytic activity have a cumulative effect on lysosome function, resulting in a lag between TRP-ML1 loss and full manifestation of mucolipidosis type IV.[TRP-ML1] (PMID:18504305)
• TRPML1 functions as a Fe(2+) permeable channel in late endosomes and lysosomes (PMID:18794901)
• a Turkish patient who, in addition to the typical characteristics of mucolipidosis type IV, defects in internal capsule, micrognathia and clinodactyly of the fifth fingers. DNA sequencing revealed a novel homozygous c.1364C>T (S456L) mutation in MCOLN1. (PMID:19006653)
• Mutations of the TRPML1 is associated with activation of the channel. (PMID:19638346)
• TRPML1 appears to play a novel role in the tissue-specific transcriptional regulation of TRPML2. (PMID:19763610)
• ALG-2 acts as a Ca(2+) sensor that modulates the function of MCOLN1 along the late endosomal-lysosomal pathway. (PMID:19864416)
• Data show that TRPMLs form distinct functional channel complexes. (PMID:19885840)
• TRPML 1, 2 and 3 assemblies regulated cell viability and starvation-induced autophagy. (PMID:20736310)
• the loss of TRPML1 function results in intracellular chelatable zinc dyshomeostasis. (PMID:20864526)
• Two members of the lysosome associated protein transmembrane (LAPTM) family were identified as novel interaction partners of mucolipin 1 (MCOLN1) (PMID:21224396)
• mucolipin-1 contributes to membrane remodeling through a serine lipase consensus domain, and thus represents a novel type of bifunctional protein. (PMID:21256127)
• molecular modulators of TRPML1 function may lead to novel approaches to modulating biological processes that depend on the endocytic pathway such as growth factor signaling (PMID:21290297)
• although TRPML1 and TPCs are present in the same complex, they function as two independent organellar ion channels and that TPCs, not TRPMLs, are the targets for NAADP. (PMID:21540176)
• NAADP increases lysosomal TRP-ML1 channel activity to release Ca(2+), which promotes the interaction of endosomes and lysosomes and thereby regulates lipid transport to lysosomes. (PMID:21613607)
• TFEB transcriptionally regulates lysosomal exocytosis both by inducing the release of intracellular Ca2+ through its target gene MCOLN1 and by increasing the population of lysosomes ready to fuse with the plasma membrane. (PMID:21889421)
• an acute siRNA-mediated loss of TRPML1 specifically causes a leak of lysosomal protease cathepsin B (CatB) into the cytoplasm. CatB leak is associated with apoptosis, which can be prevented by CatB inhibition. (PMID:22262857)
• findings show that TRPML1-mediated lysosomal Ca(2 ) release is dramatically reduced in Niemann-Pick disease cells; propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca(2 )-dependent lysosomal trafficking (PMID:22415822)
• PI(4,5)P(2) may serve as a negative cofactor for intracellular channels such as TRPML1 (PMID:22733759)
• Findings raise the possibility that the neurological dysfunction in patients with mucolipidosis type IV may arise from amino acid deprivation of TPRML in neurons. (PMID:23047439)
• TRPML1 works in concert with ZnT4 to regulate zinc translocation between the cytoplasm and lysosomes. (PMID:23368743)
• Data identified proteins as candidate TRPML1 interactors, and some false-positive interactors. (PMID:23418601)
• report of the first Saudi patient with Mucolipidosis type IV from a consanguineous family with two branches having a total of five patients carrying a novel transition mutation, c.1307A>G (p.Y436C) in exon 11 (PMID:23685283)
• Retinal pigmented epithelial cells develop a punctate phenotype within 48 hours of small interfering (si)RNA-induced TRPML1-knockdown. (PMID:24192042)
• TRPML1 has a novel role in protecting against lysosomotropic amine toxicity. (PMID:24960374)
• lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca(2+) signaling. (PMID:25733853)
• This review summarizes the current understanding of TRPML1 activation and regulation (PMID:26009188)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcoln1a	ENSDARG00000002285
danio_rerio	mcoln1b	ENSDARG00000058848
mus_musculus	Mcoln1	ENSMUSG00000004567
rattus_norvegicus	Mcoln1	ENSRNOG00000000975
drosophila_melanogaster	CG42638	FBGN0261361
drosophila_melanogaster	Trpml	FBGN0262516
caenorhabditis_elegans		WBGENE00000846

Paralogs (2): MCOLN3 (ENSG00000055732), MCOLN2 (ENSG00000153898)

Protein

Protein identifiers

Mucolipin-1 — Q9GZU1 (reviewed: Q9GZU1)

Alternative names: MG-2, Mucolipidin, Transient receptor potential channel mucolipin 1

All UniProt accessions (3): Q9GZU1, M0QXD0, M0R1X7

UniProt curated annotations — full annotation on UniProt →

Function. Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis. Acts as a Ca(2+)-permeable cation channel with inwardly rectifying activity. Proposed to play a major role in Ca(2+) release from late endosome and lysosome vesicles to the cytoplasm, which is important for many lysosome-dependent cellular events, including the fusion and trafficking of these organelles, exocytosis and autophagy. Required for efficient uptake of large particles in macrophages in which Ca(2+) release from the lysosomes triggers lysosomal exocytosis. May also play a role in phagosome-lysosome fusion. Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events. By mediating lysosomal Ca(2+) release is involved in regulation of mTORC1 signaling and in mTOR/TFEB-dependent lysosomal adaptation to environmental cues such as nutrient levels. Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy. Also functions as a Fe(2+) permeable channel in late endosomes and lysosomes. Also permeable to Mg(2+), Na(+). K(+) and Cs(+). Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells. May contribute to cellular lipase activity within the late endosomal pathway or at the cell surface which may be involved in processes of membrane reshaping and vesiculation, especially the growth of tubular structures. However, it is not known, whether it conveys the enzymatic activity directly, or merely facilitates the activity of an associated phospholipase.

Subunit / interactions. Homotetramer. Homooligomer. Can heterooligomerize with MCOLN2 or MCOLN3; heteromeric assemblies have different channel properties as compared to the respective homooligomers and may be tissue-specific. Interacts with PDCD6. Interacts with TMEM163. Interacts with LAPTM4B.

Subcellular location. Late endosome membrane. Lysosome membrane. Cytoplasmic vesicle membrane. Cell projection. Phagocytic cup. Cytoplasmic vesicle. Phagosome membrane. Cell membrane.

Tissue specificity. Widely expressed in adult and fetal tissues.

Post-translational modifications. Palmitoylated; involved in association with membranes. Phosphorylation by PKA inhibits channel activity. Dephosphorylation increases activity. Proteolytically cleaved probably involving multiple lysosomal proteases including cathepsin B; inhibits lysosomal channel activity.

Disease relevance. Mucolipidosis 4 (ML4) [MIM:252650] An autosomal recessive lysosomal storage disorder characterized by severe psychomotor retardation and ophthalmologic abnormalities, including corneal opacity, retinal degeneration and strabismus. Storage bodies of lipids and water-soluble substances are seen by electron microscopy in almost every cell type of the patients. Most patients are unable to speak or walk independently and reach a maximal developmental level of 1-2 years. All patients have constitutive achlorhydia associated with a secondary elevation of serum gastrin levels. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, Lisch epithelial (LECD) [MIM:620763] An autosomal dominant corneal dystrophy characterized by gray, band-shaped and feathery opacities in the cornea, that sometimes appear in whorled patterns. The opaque bands consist of clear, densely crowded, intra-epithelial blisters. Vision may be impaired if the bands involve the central cornea. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Channel activity is controlled by multiple regulatory mechanisms in different subcellular compartments. Channel function is transiently modulated by changes in Ca(2+) in a pH-dependent manner; pH changes modify the aggregation state of unitary channels; a negative cooperativity between extracellular/lumenal Ca(2+) and H(+) is suggested. Regulated by phosphoinositides in a compartment-specific manner: in lysosomes activated by PtdIns(3,5)P2 (Phosphatidylinositol 3,5-bisphosphate) and at the plasma membrane inhibited by PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate).

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. MCOLN1 sub-subfamily.

RefSeq proteins (1): NP_065394* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013122	PKD1_2_channel	Domain
IPR039031	Mucolipin	Family
IPR047316	ML1_ELD	Domain
IPR049134	MCLN_ECD	Domain

Pfam: PF08016, PF21381

Catalyzed reactions (Rhea), 5 shown:

• Fe(2+)(in) = Fe(2+)(out) (RHEA:28486)
• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Mg(2+)(in) = Mg(2+)(out) (RHEA:29827)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (102 total): mutagenesis site 23, helix 21, sequence variant 15, topological domain 8, strand 8, transmembrane region 6, region of interest 4, turn 4, short sequence motif 3, modified residue 3, disulfide bond 2, sequence conflict 2, chain 1, intramembrane region 1, glycosylation site 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
9HJ8	ELECTRON MICROSCOPY	2.1
9HL3	ELECTRON MICROSCOPY	2.1
9HL4	ELECTRON MICROSCOPY	2.1
9HLB	ELECTRON MICROSCOPY	2.1
9HLC	ELECTRON MICROSCOPY	2.1
9HL6	ELECTRON MICROSCOPY	2.2
9HL8	ELECTRON MICROSCOPY	2.2
9HLD	ELECTRON MICROSCOPY	2.2
5TJA	X-RAY DIFFRACTION	2.3
9HJ6	ELECTRON MICROSCOPY	2.3
9EKT	ELECTRON MICROSCOPY	2.35
5TJB	X-RAY DIFFRACTION	2.4
5TJC	X-RAY DIFFRACTION	2.4
9HLA	ELECTRON MICROSCOPY	2.4
9EKS	ELECTRON MICROSCOPY	2.42
9EKU	ELECTRON MICROSCOPY	2.68
9EKV	ELECTRON MICROSCOPY	2.75
7MGL	ELECTRON MICROSCOPY	2.9
9EB9	ELECTRON MICROSCOPY	3
9EBA	ELECTRON MICROSCOPY	3.1
5WJ9	ELECTRON MICROSCOPY	3.49
6E7P	ELECTRON MICROSCOPY	3.5
6E7Y	ELECTRON MICROSCOPY	3.57
5WJ5	ELECTRON MICROSCOPY	3.72
6E7Z	ELECTRON MICROSCOPY	3.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZU1-F1	82.18	0.50

Functional residue map

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

Post-translational modifications (3): 10, 557, 559

Disulfide bonds (2): 166–192, 253–284

Glycosylation sites (1): 230

Mutagenesis-validated functional residues (23):

Position	Phenotype
15–16	no effect on localization to lysosomes.
15	abolishes localization to lysosomes and leads to expression at the cell membrane; when associated with a-577.
42–44	reduces ptdins(4,5)p2 sensitivity.
44–46	abolishes interaction with pdcd6 and decreases formation of aberrant endosomes upon overexpression.
44	abolishes interaction with pdcd6.
45	abolishes interaction with pdcd6.
47–49	abolishes interaction with pdcd6.
61–62	reduces ptdins(3,5)p2 sensitivity.
109	abolishes formation and extrusion of tubulo-vesicular structures and decreases lysosomal exocytosis when overexpressed.
110	modulates ion conduction; when associoated with c-112 and c-113.
111	modulates inhibition by ca(2+) at different ph levels but does not abolish channel inward rectification; when associated
112	modulates ion conduction; when associoated with c-110 and c-113.
113	modulates ion conduction; when associoated with c-110 and c-112.
114	modulates inhibition by ca(2+) at different ph levels but does not abolish channel inward rectification; when associated
115	modulates inhibition by ca(2+) at different ph levels but does not abolish channel inward rectification; when associated
144	disrupts tetrameric assembly and abolishes lysosomal localization; when associated with s-146.
146	disrupts tetrameric assembly and abolishes lysosomal localization; when associated with k-144.
200	does not prevent proteolytic cleavage but changes cleavage pattern.
432	mediates localization to the plasma membrane and strong inwardly rectifying current.
471	fails to rescue defect of lactosylceramide traffic through the late endocytic pathway in ml4 patient cells.
565–567	abolishes association with membranes.
577–578	no effect on localization to lysosomes.
577	abolishes localization to lysosomes and leads to expression at the cell membrane; when associated with a-15.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-3295583	TRP channels
R-HSA-917977	Transferrin endocytosis and recycling
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-917937	Iron uptake and transport
R-HSA-983712	Ion channel transport

MSigDB gene sets: 315 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_VACUOLE_ORGANIZATION, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_VACUOLE_ORGANIZATION, KEGG_LYSOSOME, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_IRON_ION_TRANSPORT, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MACROAUTOPHAGY, GOBP_RESPONSE_TO_METAL_ION

GO Biological Process (28): adaptive immune response (GO:0002250), monoatomic cation transport (GO:0006812), intracellular zinc ion homeostasis (GO:0006882), transferrin transport (GO:0033572), iron ion transmembrane transport (GO:0034755), release of sequestered calcium ion into cytosol (GO:0051209), protein homotetramerization (GO:0051289), calcium ion transmembrane transport (GO:0070588), cellular response to calcium ion (GO:0071277), cellular response to pH (GO:0071467), phagosome maturation (GO:0090382), autophagosome maturation (GO:0097352), calcium ion export (GO:1901660), positive regulation of lysosome organization (GO:1905673), immune system process (GO:0002376), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), lysosome organization (GO:0007040), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220), sodium ion transmembrane transport (GO:0035725), negative regulation of innate immune response (GO:0045824), potassium ion transmembrane transport (GO:0071805), monoatomic cation transmembrane transport (GO:0098655), monoatomic anion transmembrane transport (GO:0098656), antibacterial innate immune response (GO:0140367), negative regulation of protein localization to nucleus (GO:1900181), positive regulation of protein localization to nucleus (GO:1900182)

GO Molecular Function (12): monoatomic anion channel activity (GO:0005253), monoatomic cation channel activity (GO:0005261), calcium channel activity (GO:0005262), potassium channel activity (GO:0005267), sodium channel activity (GO:0005272), iron ion transmembrane transporter activity (GO:0005381), lipid binding (GO:0008289), identical protein binding (GO:0042802), NAADP-sensitive calcium-release channel activity (GO:0072345), intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity (GO:0097682), ligand-gated calcium channel activity (GO:0099604), protein binding (GO:0005515)

GO Cellular Component (17): phagocytic cup (GO:0001891), nucleoplasm (GO:0005654), lysosome (GO:0005764), lysosomal membrane (GO:0005765), late endosome (GO:0005770), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), phagocytic vesicle membrane (GO:0030670), late endosome membrane (GO:0031902), signaling receptor complex (GO:0043235), intracellular vesicle (GO:0097708), endosome (GO:0005768), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Transport of small molecules	2
Stimuli-sensing channels	1
Iron uptake and transport	1
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
monoatomic cation channel activity	3
monoatomic ion transport	2
iron ion transport	2
monoatomic cation transmembrane transport	2
calcium ion transport	2
monoatomic ion channel activity	2
binding	2
ligand-gated monoatomic cation channel activity	2
endosome	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cytoplasmic vesicle	2
immune response	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
protein transport	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
protein homooligomerization	1
protein tetramerization	1
response to calcium ion	1
cellular response to metal ion	1
response to pH	1
cellular response to abiotic stimulus	1
phagolysosome assembly	1
exocytosis	1
organelle organization	1
macroautophagy	1
protein-containing complex disassembly	1
lysosome organization	1
positive regulation of vacuole organization	1
regulation of lysosome organization	1
biological_process	1
transport	1
metal ion transport	1
lytic vacuole organization	1
intracellular signaling cassette	1
transmembrane transport	1

Protein interactions and networks

STRING

1338 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCOLN1	TFEB	P19484	856
MCOLN1	FRMD6	Q96NE9	826
MCOLN1	PKD2	Q13563	781
MCOLN1	PDCD6	O75340	777
MCOLN1	NEU3	Q9UQ49	770
MCOLN1	TPCN2	Q8NHX9	762
MCOLN1	TRPM4	Q8TD43	756
MCOLN1	TRPV1	Q8NER1	754
MCOLN1	PNPLA6	Q8IY17	752
MCOLN1	TRPV2	Q9Y5S1	750
MCOLN1	GAST	P01350	723
MCOLN1	TRPA1	O75762	715
MCOLN1	TRPC5	Q9UL62	697
MCOLN1	PIKFYVE	Q9Y2I7	677
MCOLN1	TRPC1	P48995	671

IntAct

30 interactions, top by confidence:

A	B	Type	Score
MCOLN1	MCOLN1	psi-mi:“MI:0915”(physical association)	0.610
APPBP2	MCOLN1	psi-mi:“MI:0915”(physical association)	0.560
SEC22A	MCOLN1	psi-mi:“MI:0915”(physical association)	0.560
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
MCOLN1	MCOLN2	psi-mi:“MI:0914”(association)	0.530
CSGALNACT2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
MCOLN1		psi-mi:“MI:0915”(physical association)	0.460
MCOLN1		psi-mi:“MI:0403”(colocalization)	0.460
MCOLN1	GPR35	psi-mi:“MI:0915”(physical association)	0.370
CSGALNACT2	CLASP2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
MCOLN2	POTEF	psi-mi:“MI:0914”(association)	0.350
CCR6	GPR89A	psi-mi:“MI:0914”(association)	0.350
TPST2	NDC80	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
SPPL2B	HAS3	psi-mi:“MI:0914”(association)	0.350
MCOLN3	ACY3	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
MCOLN1	APPBP2	psi-mi:“MI:0915”(physical association)	0.000
SEC22A	MCOLN1	psi-mi:“MI:0915”(physical association)	0.000
MCOLN1	TRIM27	psi-mi:“MI:0915”(physical association)	0.000
MCOLN1	SLC35E1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (44): MCOLN1 (Affinity Capture-MS), MCOLN1 (Affinity Capture-MS), MCOLN1 (Affinity Capture-MS), MCOLN1 (Co-fractionation), TRIM27 (Two-hybrid), SLC35E1 (Two-hybrid), MCOLN1 (Two-hybrid), SEC22A (Two-hybrid), MCOLN1 (Two-hybrid), MCOLN1 (Phenotypic Suppression), MCOLN1 (Phenotypic Enhancement), MCOLN1 (Phenotypic Enhancement), MCOLN1 (Affinity Capture-MS), MCOLN1 (Affinity Capture-MS), MCOLN1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4P6, A1A5B4, A5PK40, A6NDV4, A6NFX1, A6NGC4, A6QL84, A6QLK4, B1AWJ5, B6ID01, E1BY51, P58749, Q2TA01, Q2YDG0, Q32PG7, Q3T9M1, Q4R7X9, Q5HZE5, Q5JZQ7, Q5R6H1, Q5RBY7, Q60HE8, Q6AY05, Q6AYM9, Q6PHN7, Q6TCG5, Q6UX01, Q6UXD7, Q7RTT9, Q7Z403, Q80ZE4, Q8CE47, Q8R139, Q8TBR7, Q96FZ5, Q96HE8, Q96S97, Q9BSA9, Q9BZW5, Q9CQC4

Diamond homologs: F6RG56, Q60HE8, Q8IZK6, Q8K595, Q8R4F0, Q8TDD5, Q99J21, Q9GZU1

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PRKACA	down-regulates	MCOLN1	phosphorylation
FIG4	“up-regulates activity”	MCOLN1
MCOLN1	“up-regulates quantity”	calcium(2+)	relocalization
MCOLN1	up-regulates	“Lysosome fusion”
TFE3	“up-regulates quantity by expression”	MCOLN1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	56
Uncertain significance	187
Likely benign	551
Benign	27

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067111	NM_020533.3(MCOLN1):c.405+1G>C	Pathogenic
1072781	NM_020533.3(MCOLN1):c.724del (p.Leu242fs)	Pathogenic
1323272	NM_020533.3(MCOLN1):c.278del (p.Phe93fs)	Pathogenic
1377765	NM_020533.3(MCOLN1):c.419del (p.Pro140fs)	Pathogenic
1386426	NM_020533.3(MCOLN1):c.948dup (p.Ala317fs)	Pathogenic
1402137	NM_020533.3(MCOLN1):c.66T>G (p.Tyr22Ter)	Pathogenic
1414260	NM_020533.3(MCOLN1):c.165del (p.Lys55fs)	Pathogenic
1451357	NM_020533.3(MCOLN1):c.230del (p.Thr77fs)	Pathogenic
1452538	NM_020533.3(MCOLN1):c.654C>A (p.Tyr218Ter)	Pathogenic
1453483	NM_020533.3(MCOLN1):c.504del (p.Tyr169fs)	Pathogenic
1455180	NM_020533.3(MCOLN1):c.844C>T (p.Gln282Ter)	Pathogenic
1456674	NC_000019.9:g.(?7587627)(7587677_?)del	Pathogenic
1460387	NM_020533.3(MCOLN1):c.507C>G (p.Tyr169Ter)	Pathogenic
1468549	NM_020533.3(MCOLN1):c.405+2T>C	Pathogenic
2005775	NM_020533.3(MCOLN1):c.1569del (p.Ile524fs)	Pathogenic
2055678	NM_020533.3(MCOLN1):c.1208_1218del (p.Arg403fs)	Pathogenic
208020	AF287270:g.511_6943del	Pathogenic
208025	NM_020533.3(MCOLN1):c.1615del (p.Ala539fs)	Pathogenic
208037	NM_020533.3(MCOLN1):c.236_237ins[NC_012920.1:m.12435_12527] (p.Gln79delinsHisHisTyrValLysSerIleValAlaSerThrPheIleIleSerLeuPheProThrThrIlePheMetCysLeuAspGlnGluValIleIleSer)	Pathogenic
208039	NM_020533.3(MCOLN1):c.920del (p.Leu307fs)	Pathogenic
2101897	NM_020533.3(MCOLN1):c.1417_1418del (p.Met473fs)	Pathogenic
2102536	NM_020533.3(MCOLN1):c.762T>G (p.Tyr254Ter)	Pathogenic
2704857	NM_020533.3(MCOLN1):c.1036del (p.Glu346fs)	Pathogenic
2710117	NM_020533.3(MCOLN1):c.507del (p.Tyr170fs)	Pathogenic
2718988	NM_020533.3(MCOLN1):c.1212C>A (p.Tyr404Ter)	Pathogenic
2749326	NM_020533.3(MCOLN1):c.1605_1606del (p.Ser535fs)	Pathogenic
2811644	NM_020533.3(MCOLN1):c.1415_1419del (p.Asp472fs)	Pathogenic
2841265	NM_020533.3(MCOLN1):c.940del (p.Leu314fs)	Pathogenic
3062182	NM_020533.3(MCOLN1):c.576C>A (p.Cys192Ter)	Pathogenic
3124442	NM_020533.3(MCOLN1):c.641dup (p.Ser214fs)	Pathogenic

SpliceAI

2050 predictions. Top by Δscore:

Variant	Effect	Δscore
19:7524959:A:AG	acceptor_gain	1.0000
19:7524960:G:GG	acceptor_gain	1.0000
19:7525162:TGCAG:T	donor_loss	1.0000
19:7525164:CAGG:C	donor_loss	1.0000
19:7525165:AGGT:A	donor_loss	1.0000
19:7525166:GGT:G	donor_loss	1.0000
19:7525167:GTGAG:G	donor_loss	1.0000
19:7525168:T:G	donor_loss	1.0000
19:7526436:CA:C	acceptor_loss	1.0000
19:7526437:A:AG	acceptor_gain	1.0000
19:7526437:AG:A	acceptor_loss	1.0000
19:7526438:G:GA	acceptor_gain	1.0000
19:7526438:GC:G	acceptor_gain	1.0000
19:7526438:GCT:G	acceptor_gain	1.0000
19:7526438:GCTC:G	acceptor_gain	1.0000
19:7526438:GCTCA:G	acceptor_gain	1.0000
19:7526567:G:GT	donor_gain	1.0000
19:7526573:GCT:G	donor_gain	1.0000
19:7526604:CAGG:C	donor_loss	1.0000
19:7526606:GG:G	donor_loss	1.0000
19:7526607:GT:G	donor_loss	1.0000
19:7526608:T:G	donor_loss	1.0000
19:7526752:T:TA	acceptor_gain	1.0000
19:7526755:CCACA:C	acceptor_loss	1.0000
19:7526756:CACA:C	acceptor_loss	1.0000
19:7526757:ACAG:A	acceptor_loss	1.0000
19:7526758:CAGTA:C	acceptor_loss	1.0000
19:7526759:A:AG	acceptor_gain	1.0000
19:7526759:A:C	acceptor_loss	1.0000
19:7526760:G:GG	acceptor_gain	1.0000

AlphaMissense

3788 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:7530286:T:C	F454L	1.000
19:7530288:C:A	F454L	1.000
19:7530288:C:G	F454L	1.000
19:7530326:T:C	L467P	1.000
19:7530333:T:A	N469K	1.000
19:7530333:T:G	N469K	1.000
19:7530334:G:T	G470W	1.000
19:7530335:G:A	G470E	1.000
19:7530335:G:T	G470V	1.000
19:7529158:T:A	W398R	0.999
19:7529158:T:C	W398R	0.999
19:7529635:T:C	F428L	0.999
19:7529637:C:A	F428L	0.999
19:7529637:C:G	F428L	0.999
19:7529681:G:A	G443D	0.999
19:7529683:T:A	W444R	0.999
19:7529683:T:C	W444R	0.999
19:7530286:T:A	F454I	0.999
19:7530287:T:C	F454S	0.999
19:7530287:T:G	F454C	0.999
19:7530317:T:C	L464P	0.999
19:7530319:T:C	F465L	0.999
19:7530321:C:A	F465L	0.999
19:7530321:C:G	F465L	0.999
19:7530326:T:A	L467H	0.999
19:7530334:G:A	G470R	0.999
19:7530334:G:C	G470R	0.999
19:7530337:G:C	D471H	0.999
19:7530338:A:C	D471A	0.999
19:7530338:A:G	D471G	0.999

dbSNP variants (sampled 300 via entrez): RS1000007534 (19:7523448 C>T), RS1000720258 (19:7532885 G>A), RS1000914166 (19:7527399 C>T), RS1001243602 (19:7527283 A>C), RS1001724594 (19:7531699 G>A,C,T), RS1001906028 (19:7532998 G>A), RS1002194633 (19:7522555 T>A,C), RS1002245893 (19:7533448 A>G), RS1002423309 (19:7527632 C>T), RS1002513613 (19:7527296 C>A), RS1002685693 (19:7529566 G>A), RS1002696372 (19:7530067 C>T), RS1002738146 (19:7529405 T>C), RS1003259243 (19:7524921 T>G), RS1003273620 (19:7524860 T>A,C)

Disease associations

OMIM: gene MIM:605248 | disease phenotypes: MIM:252650, MIM:300778, MIM:620763, MIM:270800, MIM:612020

GenCC curated gene-disease

Disease	Classification	Inheritance
mucolipidosis type IV	Definitive	Autosomal recessive
Lisch epithelial corneal dystrophy	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mucolipidosis type IV	Definitive	AR

Mondo (9): mucolipidosis type IV (MONDO:0009653), Lisch epithelial corneal dystrophy (MONDO:0010425), congenital nervous system disorder (MONDO:0002320), intellectual disability (MONDO:0001071), periventricular leukomalacia (MONDO:0015742), mucolipidosis (MONDO:0019248), hereditary spastic paraplegia 5A (MONDO:0010047), inherited retinal dystrophy (MONDO:0019118), hereditary spastic paraplegia 39 (MONDO:0012787)

Orphanet (8): Mucolipidosis type IV (Orphanet:578), Lisch epithelial corneal dystrophy (Orphanet:98955), Mucolipidosis (Orphanet:79212), Autosomal recessive spastic paraplegia type 5A (Orphanet:100986), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Autosomal recessive spastic paraplegia type 39 (Orphanet:139480), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Periventricular leukomalacia (Orphanet:171676)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000546	Retinal degeneration
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000654	Decreased light- and dark-adapted electroretinogram amplitude
HP:0000691	Microdontia
HP:0000708	Atypical behavior
HP:0000982	Palmoplantar keratoderma
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001438	Abnormal abdomen morphology
HP:0002344	Progressive neurologic deterioration
HP:0002353	EEG abnormality

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST008596_3	Opioid overdose severity score	1.000000e-08
GCST008596_6	Opioid overdose severity score	3.000000e-09
GCST010796_3101	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_3102	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-11
GCST010796_3103	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-10
GCST010796_3104	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_3105	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_3106	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_3107	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_3108	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_3109	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-11
GCST010796_3110	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3111	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3112	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-09
GCST010796_3113	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_3744	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-13
GCST010796_3745	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-10
GCST010796_3746	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_3747	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_3748	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-10
GCST010796_3749	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-12
GCST010796_3750	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST90002395_400	Mean platelet volume	3.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010140	opioid overdose severity measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007969	Leukomalacia, Periventricular	C10.228.140.300.700; C10.228.140.461.550; C14.907.253.612; C16.614.521.450
D009081	Mucolipidoses	C05.116.198.371; C10.228.140.163.100.435.590; C16.320.565.189.435.590; C16.320.565.202.670; C16.320.565.595.554.590; C18.452.132.100.435.590; C18.452.648.189.435.590; C18.452.648.202.670; C18.452.648.595.554.590
D058499	Retinal Dystrophies	C11.768.585.658
C567588	Corneal Dystrophy, Lisch Epithelial (supp.)
C567433	Spastic Paraplegia 39, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4524043 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs114077267	Toxicity	3	opioids	Overdose
rs115208233	Toxicity	3	opioids	Overdose
rs116181528	Toxicity	3	opioids	Overdose

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs115208233	MCOLN1	3	1.25	1	opioids
rs116181528	MCOLN1	3	1.50	1	opioids
rs114077267	MCOLN1	3	1.50	1	opioids

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Transient Receptor Potential channels (TRP)

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
phosphatidyl (3,5) inositol bisphosphate	Activation	7.32	pEC50
ML SA1	Activation	7.3	pEC50
MK6-83	Activation	6.96	pEC50
PRU-12	Inhibition	6.55	pIC50
PRU-10	Inhibition	6.39	pIC50
SF-22	Activation	6.3	pEC50
estradiol 3-methyl ether	Channel blocker	6.22	pIC50
ML-SA5	Activation	5.3	pEC50
SF-51	Activation	4.5	pEC50

ChEMBL bioactivities

13 potent at pChembl≥5 of 18 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.80	IC50	1600	nM	CHEMBL4856175
5.75	IC50	1800	nM	CHEMBL4875551
5.64	IC50	2300	nM	CHEMBL4847300
5.58	IC50	2600	nM	CHEMBL4856175
5.51	IC50	3100	nM	CHEMBL4856175
5.36	IC50	4400	nM	CHEMBL4855846
5.32	IC50	4800	nM	CHEMBL4855589
5.25	IC50	5600	nM	CHEMBL4857820
5.24	IC50	5700	nM	CHEMBL4870275
5.23	IC50	5900	nM	CHEMBL4851704
5.05	IC50	8900	nM	CHEMBL4874310
5.03	EC50	9400	nM	CHEMBL4856363
5.02	IC50	9500	nM	CHEMBL4851134

PubChem BioAssay actives

13 with measured affinity, of 55 total; 11 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-methoxyphenyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	1.6000	uM
N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]phenyl]benzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	1.8000	uM
N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]thiophene-2-sulfonamide	1760509: Inhibition of human TRPML1deltaNC-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-[(1S,2S)-2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	4.4000	uM
N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperidin-1-yl]cyclohexyl]benzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	4.8000	uM
N-[(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]-4-methylbenzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	5.6000	uM
N-[(1S,2S)-2-[4-[(4-methylphenyl)methyl]piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	5.7000	uM
N-[(1R,2R)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	5.9000	uM
N-[(1S,2S)-2-(4-phenylpiperidin-1-yl)cyclohexyl]benzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	8.9000	uM
N-[(1S,2S)-2-[4-(2-phenylethyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide	1760513: Activation of human TRPML1deltaNC-YFP expressed in HEK293 cells incubated for 10 mins by Fluo-4 dye calcium imaging based FLIPR analysis	ec50	9.4000	uM
N-[(1S,2S)-2-(3,4-dihydro-1H-isoquinolin-2-yl)cyclohexyl]benzenesulfonamide	1760509: Inhibition of human TRPML1deltaNC-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	9.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
bisphenol A	decreases expression, increases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	decreases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
NAADP	increases activity, affects localization	1
leucyl-leucine-methyl ester	increases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	decreases expression	1
licochalcone B	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Antimony	increases degradation, increases reaction, decreases expression, decreases reaction, increases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Calcium	affects localization, increases activity	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4819503	Binding	Inhibition of human TRPML1deltaNC-YFP expressed in HEK293 cells at 10 uM stimulated with ML-SA1 for 200 secs followed by incubation 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

29 cell lines: 12 cancer cell line, 9 finite cell line, 5 induced pluripotent stem cell, 2 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_9Q78	GM02525	Finite cell line	Female
CVCL_9Q79	GM02526	Finite cell line	Female
CVCL_9Q80	GM02527	Finite cell line	Male
CVCL_9Q81	GM02528	Finite cell line	Male
CVCL_D0MF	CENSOi063-A	Induced pluripotent stem cell	Female
CVCL_D0MG	CENSOi064-A	Induced pluripotent stem cell	Female
CVCL_D0MH	CENSOi065-A	Induced pluripotent stem cell	Male
CVCL_D0MI	CENSOi065-B	Induced pluripotent stem cell	Male
CVCL_D0MJ	CENSOi066-A	Induced pluripotent stem cell	Male
CVCL_D5F9	HeLa::TMEM192-3xHA MCOLN1 partial KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00120588	PHASE4	COMPLETED	Neuroprotection by Magnesium Sulfate Given to Women at Risk of Very Preterm Birth
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00303082	PHASE3	TERMINATED	Probiotics for the Prevention of Premature Birth and Neonatal Related Morbidity
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00413946	PHASE2	COMPLETED	Does Erythropoietin Improve Outcome in Very Preterm Infants?
NCT00589953	PHASE2	TERMINATED	High-Dose Erythropoietin in Extremely Premature Infants to Prevent/Attenuate Brain Injury: A Phase II Study
NCT02784821	PHASE2	COMPLETED	Antibiotic Dysbiosis in Preterm Infants
NCT07398872	PHASE1	ENROLLING_BY_INVITATION	Safety and Efficacy of AAV9. hMCOLN1co For Patients With Mucolipidosis Type IV
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00015782	Not specified	COMPLETED	The Natural History and Pathogenesis of Mucolipidosis Type IV
NCT01067742	Not specified	TERMINATED	The Natural History of Mucolipidosis Type IV
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05782387	Not specified	ACTIVE_NOT_RECRUITING	Mucolipidosis Type IV Natural History Study
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study