Is MLC1 p.Pro294= (c.882G>A) pathogenic?

MLC1 p.Pro294= (c.882G>A) is classified Likely benign in MLC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0699%, eas); Associated with megalencephalic leukoencephalopathy with subcortical cysts 1.

What condition is associated with MLC1 p.Pro294= (c.882G>A)?

MLC1 p.Pro294= (c.882G>A) is associated with megalencephalic leukoencephalopathy with subcortical cysts 1, megalencephalic leukoencephalopathy with subcortical cysts (ClinVar).

How common is MLC1 p.Pro294= (c.882G>A) in the general population?

MLC1 p.Pro294= (c.882G>A) is ultra-rare (popmax 0.0699%, eas) (gnomAD).

MLC1 p.Pro294=

Q: How is Megalencephalic leukoencephalopathy with subcortical cysts inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.882G>A · rs200163312 · VCV792483

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0699%, eas)

Conditions

megalencephalic leukoencephalopathy with subcortical cysts 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -2.5
Overall
CADD	0.262	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0699% East Asian · 31/44,360 alleles

Filtering AF 0.0506% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.044%

Overall 0.00236% 38/1,608,738 alleles · ultra-rare exomes 34/1,456,416 · genomes 4/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0699%	1,431
South Asian	0.0022%	45,483
Admixed American	0.00169%	59,058
European (non-Finnish)	0.000339%	294,663

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MLC1
Protein: p.Pro294=
Coding: c.882G>A
MANE Select: NM_015166
dbSNP: rs200163312
Type: single nucleotide variant
Location: chr22:50068445 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.29

Full MLC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

megalencephalic leukoencephalopathy with subcortical cysts 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: megalencephalic leukoencephalopathy with subcortical cysts

For Megalencephalic leukoencephalopathy with subcortical cysts (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

MLC1 p.Pro294Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
MLC1 c.1059+1G>A Likely pathogenic ★★ same condition
MLC1 c.321+1G>A Likely pathogenic ★★ same condition
MLC1 c.321+2T>C Likely pathogenic ★★ same condition
MLC1 c.321+2T>G Likely pathogenic ★★ same condition
MLC1 c.423+1G>A Pathogenic/Likely pathogenic ★★ same condition
MLC1 c.423+1G>T Pathogenic/Likely pathogenic ★★ same condition
MLC1 c.525+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mlc1-p-pro294 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown