MCOLN1

Chr 19ADAR

mucolipin TRP cation channel 1

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)

Primary Disease Associations & Inheritance

Lisch epithelial corneal dystrophyMIM #620763
AD
Mucolipidosis IVMIM #252650
AR
UniProtMucolipidosis 4
UniProtCorneal dystrophy, Lisch epithelial
592
ClinVar variants
71
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical SummaryMCOLN1
🧬
Gene-Disease Validity (ClinGen)
mucolipidosis type IV · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
71 Pathogenic / Likely Pathogenic· 147 VUS of 592 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.60LOEUF
pLI 0.001
Z-score 3.23
OE 0.37 (0.230.60)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.61Z-score
OE missense 0.76 (0.690.84)
272 obs / 357.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.230.60)
00.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.690.84)
00.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.15
01.21.6
LoF obs/exp: 11 / 30.1Missense obs/exp: 272 / 357.9Syn Z: -1.52

ClinVar Variant Classifications

592 submitted variants in ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic34
VUS147
Likely Benign358
Benign4
Conflicting12
37
Pathogenic
34
Likely Pathogenic
147
VUS
358
Likely Benign
4
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
0
18
0
37
Likely Pathogenic
23
2
9
0
34
VUS
2
120
18
7
147
Likely Benign
1
3
180
174
358
Benign
0
0
4
0
4
Conflicting
12
Total45125229181592

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MCOLN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MCOLN1-related mucolipidosis IV

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

MUCOLIPIN 1; MCOLN1
MIM #605248 · *

Lisch epithelial corneal dystrophy

MIM #620763

Molecular basis of disorder known

Autosomal dominant

Mucolipidosis IV

MIM #252650

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — MCOLN1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence