Is MLC1 p.Cys326= (c.978C>T) pathogenic?

MLC1 p.Cys326= (c.978C>T) is classified Benign in MLC1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 19.9%, sas) — too common for a highly-penetrant pathogenic allele; Associated with megalencephalic leukoencephalopathy with subcortical cysts 1.

What condition is associated with MLC1 p.Cys326= (c.978C>T)?

MLC1 p.Cys326= (c.978C>T) is associated with megalencephalic leukoencephalopathy with subcortical cysts 1, megalencephalic leukoencephalopathy with subcortical cysts (ClinVar).

MLC1 p.Cys326=

Q: How common is MLC1 p.Cys326= (c.978C>T) in the general population?

MLC1 p.Cys326= (c.978C>T) is common (popmax 19.9%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.978C>T · rs11568186 · VCV129617

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 19.9%, sas) — too common for a highly-penetrant pathogenic allele

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	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.1	GERP -2.1
Overall
CADD	1.866	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 19.9% South Asian · 16,914/85,044 alleles

Filtering AF 19.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.5%

Overall 12.1% 182,238/1,506,278 alleles · common exomes 165,321/1,357,424 · genomes 16,917/148,854 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	19.9%	5
Admixed American	12.8%	8
European (non-Finnish)	12.3%	8
Remaining individualsnot grpmax-eligible	12.1%	8
Amishnot grpmax-eligible	11.1%	9
Middle Eastern	11.1%	9
East Asian	8.99%	11
Finnishnot grpmax-eligible	7.57%	13
Ashkenazi Jewishnot grpmax-eligible	7.16%	14
African / African-American	6.42%	16

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.Cys326=
Coding: c.978C>T
MANE Select: NM_015166
dbSNP: rs11568186
Type: single nucleotide variant
Location: chr22:50064115 (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.Cys326Arg 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-cys326 (accessed [today's date]).

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