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…

LOFmechanismARLOEUF 1.162 OMIM phenotypes

Clinical Summary— MLC1

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Gene-Disease Validity (ClinGen)

megalencephalic leukoencephalopathy with subcortical cysts 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

153 unique Pathogenic / Likely Pathogenic· 214 VUS of 807 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MLC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.20Z-score

OE missense 0.96 (0.86–1.08)

210 obs / 218.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.49–1.16)

0≤0.351.4

Missense OE?0.96 (0.86–1.08)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 14 / 18.8Missense obs/exp: 210 / 218.4Syn Z: 0.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMLC1-related leukoencephalopathy megalencephalic with subcortical cystsLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6454th %ile

GOF

0.6930th %ile

LOF

0.3065th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

807 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48

Likely Pathogenic105

VUS214

Likely Benign318

Benign93

Conflicting19

Pathogenic

105

Likely Pathogenic

214

VUS

318

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	7	10	0	48
Likely Pathogenic	70	29	6	0	105
VUS	6	132	67	9	214
Likely Benign	0	9	138	171	318
Benign	0	3	85	5	93
Conflicting	—				19
Total	107	180	306	185	797

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

View in ClinVar →

141 pathogenic / likely-pathogenic (of 155) ClinVar copy-number / structural variants overlap MLC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →