MLC1

Summary

MLC1 (modulator of VRAC current 1, HGNC:17082) is a protein-coding gene on chromosome 22q13.33, encoding Membrane protein MLC1 (Q15049). Transmembrane protein mainly expressed in brain astrocytes that may play a role in transport across the blood-brain and brain-cerebrospinal fluid barriers.

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.

Source: NCBI Gene 23209 — RefSeq curated summary.

At a glance

• Gene–disease (curated): megalencephalic leukoencephalopathy with subcortical cysts 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 755 total — 45 pathogenic, 76 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_015166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17082
Approved symbol	MLC1
Name	modulator of VRAC current 1
Location	22q13.33
Locus type	gene with protein product
Status	Approved
Aliases	MLC, KIAA0027, LVM, VL
Ensembl gene	ENSG00000100427
Ensembl biotype	protein_coding
OMIM	605908
Entrez	23209

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 16 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000311597, ENST00000395876, ENST00000442311, ENST00000470008, ENST00000483836, ENST00000879262, ENST00000879263, ENST00000879264, ENST00000879265, ENST00000879267, ENST00000879269, ENST00000879270, ENST00000879271, ENST00000879272, ENST00000879273, ENST00000879274, ENST00000879275, ENST00000879276

RefSeq mRNA: 15 — MANE Select: NM_015166 NM_001376472, NM_001376473, NM_001376474, NM_001376475, NM_001376476, NM_001376477, NM_001376478, NM_001376479, NM_001376480, NM_001376481, NM_001376482, NM_001376483, NM_001376484, NM_015166, NM_139202

CCDS: CCDS14083

Canonical transcript exons

ENST00000311597 — 12 exons

Exon	Start	End
ENSE00000657483	50077401	50077502
ENSE00000657485	50079918	50080019
ENSE00000657488	50084726	50084961
ENSE00001287429	50076841	50076912
ENSE00001321578	50083084	50083173
ENSE00001329286	50080344	50080397
ENSE00001860689	50085355	50085426
ENSE00003536353	50064034	50064198
ENSE00003651096	50068433	50068555
ENSE00003670606	50070527	50070583
ENSE00003672847	50074216	50074332
ENSE00003900633	50059391	50061657

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 97.78.

FANTOM5 (CAGE): breadth broad, TPM avg 11.6994 / max 421.7360, expressed in 423 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194694	3.6868	308
194693	2.6743	147
194690	1.6331	144
194692	1.2781	113
194689	0.6641	137
194695	0.6242	173
194696	0.2710	100
194688	0.2396	97
194687	0.1926	102
194699	0.1342	73

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	97.78	gold quality
ventricular zone	UBERON:0003053	97.57	gold quality
caudate nucleus	UBERON:0001873	97.45	gold quality
amygdala	UBERON:0001876	97.44	gold quality
putamen	UBERON:0001874	97.06	gold quality
right frontal lobe	UBERON:0002810	97.02	gold quality
paraflocculus	UBERON:0005351	95.97	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.67	gold quality
anterior cingulate cortex	UBERON:0009835	95.55	gold quality
cingulate cortex	UBERON:0003027	95.52	gold quality
hypothalamus	UBERON:0001898	94.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.60	gold quality
ganglionic eminence	UBERON:0004023	94.05	gold quality
Ammon’s horn	UBERON:0001954	93.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.45	gold quality
temporal lobe	UBERON:0001871	93.38	gold quality
telencephalon	UBERON:0001893	93.27	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.85	gold quality
spinal cord	UBERON:0002240	92.76	gold quality
substantia nigra	UBERON:0002038	92.67	gold quality
cerebellar cortex	UBERON:0002129	92.58	gold quality
cerebellar hemisphere	UBERON:0002245	92.57	gold quality
middle frontal gyrus	UBERON:0002702	92.56	gold quality
prefrontal cortex	UBERON:0000451	92.16	gold quality
granulocyte	CL:0000094	92.10	gold quality
frontal cortex	UBERON:0001870	91.96	gold quality
frontal lobe	UBERON:0016525	91.96	gold quality
cerebellum	UBERON:0002037	91.91	gold quality
neocortex	UBERON:0001950	91.86	gold quality
cerebral cortex	UBERON:0000956	91.83	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	947.37
E-GEOD-137537	yes	704.24
E-MTAB-6075	yes	488.91
E-MTAB-9067	yes	15.93
E-GEOD-93593	yes	13.70
E-ANND-3	yes	5.82
E-MTAB-9801	yes	4.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA4, MYOD1, MYOG, STAT1

miRNA regulators (miRDB)

43 targeting MLC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-6503-5P	99.62	66.96	597
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. (PMID:11935341)
• a novel polymorphism in exon 11 of the gene shows no association with schizophrenia (PMID:12111645)
• physical and functional interaction with fortilin: its potential role as a fortilin chaperone (PMID:12149273)
• KIAA0027 alleles were evaluated for potential roles in susceptibility to megalencephalic leukoencephalopathy and schizophrenia. (PMID:12497630)
• A 41-year-old Japanese male with MLC, in whom a homozygous missense mutation, TCG to TTG at codon 93 resulting in S93L, was detected in the MLC1 gene (PMID:12850517)
• A broad spectrum of pathogenetic mutations (missense, splice site, insertion, and deletions) were identified in the MLC1 gene, enlarging the spectrum of allelic variants without a straightforward genotype-phenotype correlation. (PMID:12939431)
• MLC1 may have a role in van der Knaap disease; it is mutated in patients (PMID:14615938)
• Thirty-three affected individuals with MLC were screened. All were from northern India and included 31 known Agarwals. All Agarwal patients were positive for homozygous insertion of a cytosine in exon 2 (PMID:15037685)
• Association of MLC1 with SCZ and BPAD suggests involvement of a common pathway. (PMID:15992519)
• MLC1 gene showed up-regulation expression at both the mRNA and protein levels in HCC tissues and that MLC1 plays an important role in the growth of hepatoma cell SMMC7721 in vitro and vivo. (PMID:16001658)
• analysis of novel variants in MLC1 in patients with vacuolating megalencephalic leukoencephalopathy with subcortical cysts (PMID:16470554)
• 13 novel mutations are associated with Megalencephalic leukoencephalopathy with subcortical cysts. (PMID:16652334)
• in the human brain, MLC1 protein is expressed in astrocyte processes and ependymal cells, where it colocalizes with dystroglycan and syntrophin (PMID:18165104)
• Prenatal diagnosis of megalencephalic leukodystrophy. (PMID:18330867)
• Because pathological mutations prevent MLC1 membrane expression, the identification of substances regulating MLC1 intracellular trafficking is potentially relevant for the therapy of MLC. (PMID:19931615)
• We report two patients with megalencephalic leukoencephalopathy with subcortical cysts with confirmed mutations in the MLC1 gene. The mutation in the second patient was novel. We also review identified mutations in the Turkish population. (PMID:20560255)
• through its interaction with ATP1B1, MLC1 is involved in the control of intracellular osmotic conditions and volume regulation in astrocytes, opening new perspectives for understanding the pathological mechanisms of MLC disease. (PMID:20926452)
• Study detected five novel nucleotide variations in the entire coding region of the MLC1 gene. (PMID:21145992)
• Identification of novel MLC1 mutations in Chinese patients with megalencephalic leukoencephlopathy with subcortical cysts is reported. (PMID:21160490)
• Reduction of MLC1 expression results in the appearance of astrocyte intracellular vacuoles. This vacuolation is reversed by the co-expression of human MLC1 (PMID:21440627)
• The presence of the c.135_136insC mutation in 29 patients of the Agarwal community suggests a founder effect in Indian patients. (PMID:21555057)
• study presents more detailed characterization of the effect of mutations found in MLC1 and GLIALCAM megalencephalic leukoencephalopathy with subcortical cysts (PMID:21624973)
• that MLC1 plays a role in astrocyte osmo-homeostasis and that defects in intracellular calcium dynamics may contribute to MLC pathogenesis. (PMID:22328087)
• Data show that wildtype MLC1(wt) was localized to the cell periphery, whereas mutant R22Q, A32V, G73E, S69L and T118M were trapped in the lumen of endoplasmic reticulum (ER). (PMID:22416245)
• Proposed is a therapeutic approach for prevention of cardiac contractile dysfunction dependent on MLC1 phosphorylation and degradation. (PMID:23495687)
• results indicate GlialCAM is necessary for MLC1 protein expression, and its reduction affects the activity of volume-regulated anion currents (VRAC) which may cause astrocyte vacuolation; work extends the role of GlialCAM as a chaperone of MLC1 needed for proper VRAC activation (PMID:23793458)
• clinical spectrum, neuroimaging characteristics and gene involvement in Egyptian patients with megalencephalic leukoencephalopathy with subcortical cysts; deletion/insertion mutation in exon 11 was recurrent in 2 families; a missense mutation in exon 10 was identified in the third family (PMID:24315536)
• This study shows that in astrocytes MLC1 is expressed in early endosomes and recycled through the Rab11+ perinuclear compartment (PMID:24561067)
• we demonstrate an evolutionary conserved role for MLC1 in regulating glial surface levels of GLIALCAM, and this interrelationship explains why patients with mutations in either gene (MLC1 or GLIALCAM) share the same clinical phenotype. (PMID:24824219)
• Eight novel mutations in MLC1 from 18 Iranian patients with megalencephalic leukoencephalopathy with subcortical cysts (PMID:25497041)
• Gene sequencing identified two heterozygous mutations of MLC1, including missense mutation in exon 3 (c.217G>A, p.Gly73Arg) and splice site mutation in intron 9 (c.772-1G>C in IVS9-1). (PMID:25919557)
• The extracellular domain of GlialCAM is necessary for cell junction targeting and for mediating interactions with itself or with MLC1 and ClC-2. (PMID:26033718)
• Study discloses an important role for MLC1 in the control of astrocyte growth and in the regulation of pathways that trigger quiescent astrocytes into reactive ones in response to brain injury. It also shows that MLC1 pathological mutations cause loss of its function, opening new perspectives for the comprehension of MLC disease pathogenesis. (PMID:26908604)
• Out of 20 patients, macrocephaly, classic MRI features, motor development delay and cognitive impairment were detected in 20(100%), 20(100%), 17(85%) and 4(20%) patients, respectively. 20(100%) were clinically diagnosed with MLC. 19(95%) were genetically diagnosed with 10 novel mutations in MLC1, MLC1 and GlialCAM mutations were identified in 15 and 4 patients, respectively (PMID:27322623)
• Novel mutations were identified in MLC1 from a group of Egyptian patients with megalencephalic leukoencephalopathy. (PMID:27389245)
• Three different MLC1 pathogenic variants from five MLC patients with seven alleles contained the p.Ala275Asp variant in exon 10, two frameshift variants p.(Cys46Alafs*12) and p.(Ile113Glyfs*4) were also identified. (PMID:28840990)
• Disturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures (PMID:29466841)
• The frequency of MLC1 c.736delA in multiple families with similar disease phenotype from the Nalband community suggests a founder effect. (PMID:29667716)
• three overlapping genes (FGFBP2, GFOD1 and MLC1) between two modules could potentially have a role in acute myocardial infarction and have diagnostic potential (PMID:30683112)
• MLC1 contributes to restore astrocyte homeostasis after inflammation. (PMID:31209783)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mlc1	ENSDARG00000063026
mus_musculus	Mlc1	ENSMUSG00000035805
rattus_norvegicus	Mlc1	ENSRNOG00000032871

Protein

Protein identifiers

Membrane protein MLC1 — Q15049 (reviewed: Q15049)

Alternative names: Megalencephalic leukoencephalopathy with subcortical cysts protein 1

All UniProt accessions (2): Q15049, A6PVC3

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane protein mainly expressed in brain astrocytes that may play a role in transport across the blood-brain and brain-cerebrospinal fluid barriers. Regulates the response of astrocytes to hypo-osmosis by promoting calcium influx. May function as regulatory protein of membrane protein complexes such as ion channels.

Subunit / interactions. Interacts with ATP1B1. Part of a complex containing ATP1B1, TRPV4, AQP4 and HEPACAM.

Subcellular location. Membrane. Cell membrane. Cytoplasm. Perinuclear region. Endoplasmic reticulum.

Tissue specificity. Expressed in the brain, with highest levels found in the amygdala, nucleus caudatus, thalamus and hippocampus.

Disease relevance. Megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) [MIM:604004] A syndrome of cerebral leukoencephalopathy and megalencephaly characterized by ataxia, spasticity, seizures, delay in motor development and mild intellectual disability. The brain appears swollen on magnetic resonance imaging, with diffuse white-matter abnormalities and the invariable presence of subcortical cysts in frontal and temporal lobes. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15049-1	1	yes
Q15049-2	2

RefSeq proteins (15): NP_001363401, NP_001363402, NP_001363403, NP_001363404, NP_001363405, NP_001363406, NP_001363407, NP_001363408, NP_001363409, NP_001363410, NP_001363411, NP_001363412, NP_001363413, NP_055981, NP_631941 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033280	Membrane_MLC1	Family

UniProt features (34 total): sequence variant 18, transmembrane region 8, modified residue 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15049-F1	71.29	0.31

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 177, 179

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 171 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_16, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_TRANSPORT, NIKOLSKY_BREAST_CANCER_22Q13_AMPLICON, MODULE_66, MODULE_118, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_RESPONSE_TO_STEROL, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, GOCC_COATED_VESICLE, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (6): protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), positive regulation of intracellular transport (GO:0032388), regulation of response to osmotic stress (GO:0047484), cellular response to cholesterol (GO:0071397), caveolin-mediated endocytosis (GO:0072584)

GO Molecular Function (3): identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (17): cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), caveola (GO:0005901), cell-cell junction (GO:0005911), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), cytoplasmic vesicle (GO:0031410), membrane raft (GO:0045121), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), astrocyte end-foot (GO:0097450)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	4
transport	2
binding	2
endomembrane system	2
endosome	2
plasma membrane region	2
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
regulation of intracellular transport	1
intracellular transport	1
positive regulation of cellular process	1
positive regulation of transport	1
response to osmotic stress	1
regulation of response to stress	1
cellular response to sterol	1
response to cholesterol	1
cellular response to alcohol	1
endocytosis	1
protein binding	1
intracellular anatomical structure	1
lytic vacuole	1
cytoplasmic vesicle	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
plasma membrane raft	1
anchoring junction	1
basal plasma membrane	1
apical part of cell	1
intracellular vesicle	1
membrane microdomain	1
astrocyte projection	1

Protein interactions and networks

STRING

548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MLC1	MYL1	P05976	872
MLC1	MYL6	P16475	849
MLC1	MYL6B	P14649	828
MLC1	GSTP1	P09211	683
MLC1	HEPACAM	Q14CZ8	435
MLC1	MPPE1	Q53F39	429
MLC1	CKAP2	Q8WWK9	407
MLC1	KRCC1	Q9NPI7	400
MLC1	SLC2A4RG	Q9NR83	376
MLC1	ZNF704	Q6ZNC4	350
MLC1	PPP1CC	P36873	349
MLC1	MYL12B	O14950	324
MLC1	CDC14B	O60729	323
MLC1	TBXA2R	P21731	310
MLC1	TMEM106A	Q96A25	287

IntAct

53 interactions, top by confidence:

A	B	Type	Score
MLC1	DR1	psi-mi:“MI:0915”(physical association)	0.560
MLC1	GFAP	psi-mi:“MI:0915”(physical association)	0.560
GTF2B	MLC1	psi-mi:“MI:0915”(physical association)	0.560
MLC1	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
MLC1	NEFL	psi-mi:“MI:0915”(physical association)	0.560
MLC1	PRPS1	psi-mi:“MI:0915”(physical association)	0.560
MLC1	WFS1	psi-mi:“MI:0915”(physical association)	0.560
MLC1	GTF3C3	psi-mi:“MI:0915”(physical association)	0.560
MLC1	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
MLC1	ATXN10	psi-mi:“MI:0915”(physical association)	0.560
MLC1	RNF11	psi-mi:“MI:0915”(physical association)	0.560
MLC1	JPH3	psi-mi:“MI:0915”(physical association)	0.560
TARDBP	MLC1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (29): MLC1 (Biochemical Activity), KCNJ10 (Affinity Capture-Western), PTGES2 (Affinity Capture-MS), FGFR1 (Affinity Capture-MS), MLC1 (Biochemical Activity), NOMO1 (Affinity Capture-MS), MZT2B (Affinity Capture-MS), LETM1 (Affinity Capture-MS), VAMP3 (Affinity Capture-MS), YTHDF1 (Affinity Capture-MS), MDC1 (Affinity Capture-MS), MLC1 (Positive Genetic), MLC1 (Two-hybrid), MLC1 (Affinity Capture-MS), MLC1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A218N034, A0A482AU60, F1QHM7, F1QX91, F5H9I4, F5H9N9, F5HAR3, F5HD92, F5HDD0, F5HE44, F5HE69, F5HET1, F5HFH0, F5HGH8, F5HHT6, J7FIP9, J7FJH0, O13980, P03215, P04288, P09298, P09716, P09717, P09718, P09719, P09720, P09721, P09723, P09724, P0DUR6, P16751, P28948, P52373, P69334, P69335, P69336, P69337, P89433, P89443, P98999

Diamond homologs: Q15049, Q60HE7, Q8VHK5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

755 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	76
Uncertain significance	203
Likely benign	284
Benign	91

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1332811	NM_015166.4(MLC1):c.368C>T (p.Thr123Ile)	Pathogenic
1362299	NM_015166.4(MLC1):c.705_712delCCTAGTGG (p.Val237fs)	Pathogenic
1416197	NM_015166.4(MLC1):c.335del (p.Gln112fs)	Pathogenic
1442600	NM_015166.4(MLC1):c.119C>A (p.Ser40Ter)	Pathogenic
1691319	NM_015166.4(MLC1):c.736del (p.Ser246fs)	Pathogenic
1702863	NM_015166.4(MLC1):c.908_918delinsGCA (p.Val303fs)	Pathogenic
189169	NM_015166.4(MLC1):c.324del (p.Asn110fs)	Pathogenic
2004626	NM_015166.4(MLC1):c.822del (p.Ala275fs)	Pathogenic
202208	NM_015166.4(MLC1):c.223del (p.Val75fs)	Pathogenic
2034654	NM_015166.4(MLC1):c.163del (p.Ser55fs)	Pathogenic
2074979	NM_015166.4(MLC1):c.423+2T>G	Pathogenic
2126589	NM_015166.4(MLC1):c.481_524del (p.Ile161fs)	Pathogenic
2138460	NM_015166.4(MLC1):c.135del (p.Cys46fs)	Pathogenic
2160757	NM_015166.4(MLC1):c.735del (p.Ser246fs)	Pathogenic
2426086	NC_000022.10:g.(?50523145)(50523373_?)del	Pathogenic
2426087	NC_000022.10:g.(?50500012)(50515951_?)del	Pathogenic
2426090	NC_000022.10:g.(?50518954)(50523273_?)del	Pathogenic
2426091	NC_000022.10:g.(?50500002)(50523373_?)del	Pathogenic
242875	NM_015166.4(MLC1):c.617G>T (p.Gly206Val)	Pathogenic
2676575	NM_015166.4(MLC1):c.772-1G>C	Pathogenic
2711026	NM_015166.4(MLC1):c.345dup (p.Val116fs)	Pathogenic
2759060	NM_015166.4(MLC1):c.850_851del (p.Met284fs)	Pathogenic
2907563	NM_015166.4(MLC1):c.912_935del (p.Leu307_Leu314del)	Pathogenic
3248120	NC_000022.10:g.(?50506842)(50507004_?)del	Pathogenic
3248121	NC_000022.10:g.(?50521493)(50523373_?)del	Pathogenic
3248122	NC_000022.10:g.(?50518337)(50523373_?)del	Pathogenic
3248123	NC_000022.10:g.(?50512625)(50518846_?)del	Pathogenic
3248124	NC_000022.10:g.(?50508936)(50512781_?)del	Pathogenic
3248125	NC_000022.10:g.(?50518239)(50518795_?)del	Pathogenic
3633075	NM_015166.4(MLC1):c.702del (p.Phe233_Trp234insTer)	Pathogenic

SpliceAI

2090 predictions. Top by Δscore:

Variant	Effect	Δscore
22:50060163:C:CT	acceptor_gain	1.0000
22:50061656:ACCTG:A	acceptor_loss	1.0000
22:50061659:T:A	acceptor_loss	1.0000
22:50068429:TCACT:T	donor_loss	1.0000
22:50068430:CACTT:C	donor_loss	1.0000
22:50068431:A:AC	donor_gain	1.0000
22:50068432:C:CC	donor_gain	1.0000
22:50074214:A:AC	donor_gain	1.0000
22:50074215:C:CC	donor_gain	1.0000
22:50076839:A:AC	donor_gain	1.0000
22:50076840:C:CC	donor_gain	1.0000
22:50077397:CCA:C	donor_loss	1.0000
22:50077398:CA:C	donor_loss	1.0000
22:50077399:A:AC	donor_gain	1.0000
22:50077400:C:CC	donor_gain	1.0000
22:50077400:C:CT	donor_loss	1.0000
22:50077400:CCTT:C	donor_gain	1.0000
22:50077498:TTGAT:T	acceptor_gain	1.0000
22:50077499:TGAT:T	acceptor_gain	1.0000
22:50077500:GAT:G	acceptor_gain	1.0000
22:50077502:TCT:T	acceptor_loss	1.0000
22:50077503:C:CC	acceptor_gain	1.0000
22:50077503:CTGCC:C	acceptor_loss	1.0000
22:50077504:T:A	acceptor_loss	1.0000
22:50077507:C:CT	acceptor_gain	1.0000
22:50079916:A:AC	donor_gain	1.0000
22:50079917:C:CC	donor_gain	1.0000
22:50083082:A:AC	donor_gain	1.0000
22:50083083:C:CC	donor_gain	1.0000
22:50083083:CAGAG:C	donor_gain	1.0000

AlphaMissense

2434 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:50068529:G:C	S266R	0.997
22:50068529:G:T	S266R	0.997
22:50068531:T:G	S266R	0.997
22:50074230:A:G	W234R	0.995
22:50074230:A:T	W234R	0.995
22:50061631:G:C	F362L	0.994
22:50061631:G:T	F362L	0.994
22:50061633:A:G	F362L	0.994
22:50079968:A:G	C125R	0.994
22:50061605:A:T	V371D	0.993
22:50070560:A:C	S246R	0.993
22:50070560:A:T	S246R	0.993
22:50070562:T:G	S246R	0.993
22:50079954:A:C	F129L	0.993
22:50079954:A:T	F129L	0.993
22:50079956:A:G	F129L	0.993
22:50079959:A:G	W128R	0.992
22:50079959:A:T	W128R	0.992
22:50079984:A:C	F119L	0.992
22:50079984:A:T	F119L	0.992
22:50079986:A:G	F119L	0.992
22:50083098:A:G	C85R	0.992
22:50061615:A:G	W368R	0.991
22:50061615:A:T	W368R	0.991
22:50083094:G:T	A86D	0.991
22:50061613:C:A	W368C	0.990
22:50061613:C:G	W368C	0.990
22:50070572:A:C	S242R	0.990
22:50070572:A:T	S242R	0.990
22:50070574:T:G	S242R	0.990

dbSNP variants (sampled 300 via entrez): RS1000022542 (22:50073255 G>A,C), RS1000053070 (22:50079716 A>G), RS1000083571 (22:50079340 T>A,C,G), RS1000083691 (22:50086852 A>G), RS1000323577 (22:50074539 T>A,C), RS1000395592 (22:50084325 A>G), RS1000416221 (22:50070315 G>A), RS1000480738 (22:50085407 A>G), RS1000517115 (22:50065418 A>G), RS1000595034 (22:50064268 G>A,C,T), RS1000598331 (22:50061424 T>G), RS1000700730 (22:50071158 G>T), RS1000947161 (22:50084114 A>G), RS1000959550 (22:50065092 T>C), RS1000990423 (22:50060370 C>G)

Disease associations

OMIM: gene MIM:605908 | disease phenotypes: MIM:604004

GenCC curated gene-disease

Disease	Classification	Inheritance
megalencephalic leukoencephalopathy with subcortical cysts 1	Definitive	Autosomal recessive
megalencephalic leukoencephalopathy with subcortical cysts	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
megalencephalic leukoencephalopathy with subcortical cysts 1	Definitive	AR

Mondo (3): megalencephalic leukoencephalopathy with subcortical cysts 1 (MONDO:0024555), megalencephalic leukoencephalopathy with subcortical cysts (MONDO:0011391), congenital nervous system disorder (MONDO:0002320)

Orphanet (1): Megalencephalic leukoencephalopathy with subcortical cysts (Orphanet:2478)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001332	Dystonia
HP:0001355	Megalencephaly
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002133	Status epilepticus
HP:0002305	Athetosis
HP:0002312	Clumsiness
HP:0002317	Unsteady gait
HP:0002333	Motor deterioration
HP:0003593	Infantile onset
HP:0005490	Postnatal macrocephaly
HP:0006943	Diffuse spongiform leukoencephalopathy
HP:0007341	Diffuse swelling of cerebral white matter
HP:0012762	Cerebral white matter atrophy
HP:6000461	Cerebral subcortical cyst

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002481_12	Acne (severe)	4.000000e-06
GCST004519_4	Body mass index (adult)	3.000000e-09
GCST012490_608	Femur bone mineral density x serum urate levels interaction	6.000000e-09
GCST012490_69	Femur bone mineral density x serum urate levels interaction	7.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536141	Megalencephalic leukoencephalopathy with subcortical cysts (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523299 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, affects methylation	2
Cadmium	increases abundance, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
aflatoxin B2	increases methylation	1
gallium arsenide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
spiromesifen	decreases expression	1
Vorinostat	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	decreases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	increases expression	1
Dronabinol	decreases expression	1
Thiram	increases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4335414	Binding	Binding affinity to MLC1 in human Huh7.5.1 cell lysate infected with HCV at 0.1 to 10 uM incubated for 1 hr followed by 10000 mJ/cm2 UV irradiation for 10 mins and subsequent addition of biotin-N3 measured after 1 hr by ABPP Gel-based by LC	Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors. — J Med Chem

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project