MLC1

Chr 22AR

modulator of VRAC current 1

Also known as: LVM, MLC, VL

NCBI Gene: 23209 ENSG00000100427 UniProt: Q15049 OMIM: 605908

This gene encodes a transmembrane protein expressed in brain astrocytes that regulates astrocyte response to hypo-osmotic conditions and may function in transport across blood-brain and cerebrospinal fluid barriers. Mutations cause megalencephalic leukoencephalopathy with subcortical cysts, a progressive white matter disorder typically presenting in infancy with macrocephaly. The condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Megalencephalic leukoencephalopathy with subcortical cysts 1MIM #604004

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · megalencephalic leukoencephalopathy with subcortical cysts 1 · AR · ClinGen 2024

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)

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P/LP submissions

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P/LP missense

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LOEUF

LOF

Mechanism· G2P

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GeneReview available — MLC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

gnomad: Error: Service overloaded

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in MLC1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

494 rare PASS variants

Rare truncating (LoF)

1 in 2,000

80 rare PASS variants

Rare synonymous (reference)

1 in 250

201 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MLC1. 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 130	1 in 1,900
South Asian	~43k	1 in 110	1 in 940
Remaining (unassigned)	~30k	1 in 75	1 in 6,000
European (Finnish)	~27k	1 in 470	1 in 3,100
Admixed American	~22k	1 in 93	≈ 1 in 10,000
African / African American	~21k	1 in 130	1 in 1,000
East Asian	~20k	1 in 110	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 1,300	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 90	≈ 1 in 940

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.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓