MLC1

Chr 22AR

modulator of VRAC current 1

Also known as: LVM, MLC, VL

NCBI Gene: 23209ENSG00000100427UniProt: Q15049

The function of this gene product is unknown; however, homology to other proteins suggests that it may be an integral membrane transporter. Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Megalencephalic leukoencephalopathy with subcortical cysts 1MIM #604004
AR
Megalencephalic leukoencephalopathy with subcortical cysts 1MIM #604004
AR
494
ClinVar variants
132
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— MLC1
🧬
Gene-Disease Validity (ClinGen)
megalencephalic leukoencephalopathy with subcortical cysts 1 · 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
132 Pathogenic / Likely Pathogenic· 141 VUS of 494 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
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.
1.16LOEUF
pLI 0.000
Z-score 1.03
OE 0.74 (0.49–1.16)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.20Z-score
OE missense 0.96 (0.86–1.08)
210 obs / 218.4 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.0.74 (0.49–1.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.86–1.08)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 14 / 18.8Missense obs/exp: 210 / 218.4Syn Z: 0.41

ClinVar Variant Classifications

494 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic80
Likely Pathogenic52
VUS141
Likely Benign184
Benign31
Conflicting6
80
Pathogenic
52
Likely Pathogenic
141
VUS
184
Likely Benign
31
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
1
66
0
80
Likely Pathogenic
34
11
7
0
52
VUS
0
95
41
5
141
Likely Benign
0
3
108
73
184
Benign
0
0
31
0
31
Conflicting
—6
Total4711025378494

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

View in ClinVar →

Protein Context — Lollipop Plot

MLC1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MLC1-related leukoencephalopathy megalencephalic with subcortical cysts

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Megalencephalic leukoencephalopathy with subcortical cysts 1

MIM #604004

Molecular basis of disorder known

Autosomal recessive

Megalencephalic leukoencephalopathy with subcortical cysts 1

MIM #604004

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — MLC1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema.
Passchier EMJ et al.·Brain
2023
MLC1 Overexpression Inhibits Tumor Progression through PI3K/AKT Signal Pathway in Prostate Cancer.
Wu Z et al.·Adv Biol (Weinh)
2024
Leukodystrophies with astrocytic dysfunction.
Rodriguez D·Handb Clin Neurol
2013Review
Modulator of VRAC Current 1 Is a Potential Target Antigen in Multiple Sclerosis.
Dahl JR et al.·Neurol Neuroimmunol Neuroinflamm
2025
Homozygous variant of MLC1 results in megalencephalic leukoencephalopathy with subcortical cysts.
Zha J et al.·Mol Genet Genomic Med
2024
Plasma membrane localization of MLC1 regulates cellular morphology and motility.
Hwang J et al.·Mol Brain
2019
A homozygous missense variant in the MLC1 gene underlies megalencephalic leukoencephalopathy with subcortical cysts in large kindred: Heterozygous carriers show seizure and mild motor function deterioration.
Ain Ul Batool S et al.·Am J Med Genet A
2022
Megalencephalic leukoencephalopathy with subcortical cysts.
Singhal BS et al.·J Child Neurol
2003Review
Prevalent MLC1 mutation causing autosomal recessive megalencephalic leukoencephalopathy in consanguineous Palestinian families.
Khalaf-Nazzal R et al.·Brain Dev
2022
Regulation of the orphan G-protein-coupled receptor GPRC5B by MLC1 and the cell adhesion molecule GlialCAM in megalencephalic leukoencephalopathy.
Pont-Espinós G et al.·J Biol Chem
2026
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
LeukodystrophyWhite Matter DiseaseLeukoencephalopathies

The Myelin Disorders Biorepository Project

RECRUITING
NCT03047369Children's Hospital of PhiladelphiaStarted 2016-12-08

External Resources

Links to major genomics databases and tools