MCOLN1

Chr 19ADAR

mucolipin TRP cation channel 1

ENSG00000090674 UniProt: Q9GZU1 OMIM: 605248

This gene encodes a TRP cation channel that localizes to lysosomal and late endosomal membranes, where it transports calcium, iron, sodium, potassium, and hydrogen ions to regulate lysosomal exocytosis and the late endocytic pathway. Mutations cause mucolipidosis type IV through autosomal recessive inheritance and Lisch epithelial corneal dystrophy through autosomal dominant inheritance. The pathogenic mechanism involves gain-of-function changes to the channel's ion transport properties.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis (PubMed:11013137, PubMed:12459486, PubMed:14749347, PubMed:15336987, PubMed:18794901, PubMed:25720963, PubMed:27623384, PubMed:29019983). Acts as a Ca(2+)-permeable cation channel with inwardly rectifying activity (PubMed:25720963, PubMed:29019983). 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 (PubMed:11013137, PubMed:12459486, PubMed:14749347, PubMed:15336987, PubMed:25720963, PubMed:27623384, PubMed:29019983). 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 (By similarity). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events (PubMed:16978393). 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 (PubMed:25720963, PubMed:25733853, PubMed:27787197). Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy (PubMed:27357649). Also functions as a Fe(2+) permeable channel in late endosomes and lysosomes (PubMed:18794901). Also permeable to Mg(2+), Na(+), K(+) and Cs(+) (By similarity). Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 (PubMed:25130899) In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (By similarity)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Lisch epithelial corneal dystrophyMIM #620763

Mucolipidosis IVMIM #252650

UniProtMucolipidosis 4

UniProtCorneal dystrophy, Lisch epithelial

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mucolipidosis type IV · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.60

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.60LOEUF

pLI 0.001

Z-score 3.23

OE 0.37 (0.23–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.61Z-score

OE missense 0.76 (0.69–0.84)

272 obs / 357.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.23–0.60)

0≤0.351.4

Missense OE?0.76 (0.69–0.84)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 11 / 30.1Missense obs/exp: 272 / 357.9Syn Z: -1.52

Background carrier burden — how many people carry a rare variant somewhere in MCOLN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 61

722 rare PASS variants

Rare truncating (LoF)

1 in 890

109 rare PASS variants

Rare synonymous (reference)

1 in 140

347 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MCOLN1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 87	1 in 1,300
South Asian	~43k	1 in 78	1 in 350
Remaining (unassigned)	~30k	1 in 50	1 in 640
European (Finnish)	~27k	1 in 160	≈ 1 in 13,000
Admixed American	~22k	1 in 79	1 in 630
African / African American	~21k	1 in 72	1 in 1,400
East Asian	~20k	1 in 100	1 in 2,000
Ashkenazi Jewish	~13k	1 in 350	1 in 1,200
Middle Eastern	~2,884	1 in 66	≈ 1 in 900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.