Is MLC1 p.Ser332= (c.996T>C) pathogenic?

MLC1 p.Ser332= (c.996T>C) is classified Benign in MLC1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 19.8%, sas) — too common for a highly-penetrant pathogenic allele; Associated with megalencephalic leukoencephalopathy with subcortical cysts 1.

What condition is associated with MLC1 p.Ser332= (c.996T>C)?

MLC1 p.Ser332= (c.996T>C) is associated with megalencephalic leukoencephalopathy with subcortical cysts 1, megalencephalic leukoencephalopathy with subcortical cysts (ClinVar).

MLC1 p.Ser332=

Q: How common is MLC1 p.Ser332= (c.996T>C) in the general population?

MLC1 p.Ser332= (c.996T>C) is common (popmax 19.8%, 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.996T>C · rs11568187 · VCV129618

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 19.8%, 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/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.68	donor loss · deltas
Constraint at this position
Conservation	phyloP -2.4	GERP -1.6
Overall
CADD	1.799	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 19.8% South Asian · 16,894/85,252 alleles

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

Overall 12% 181,837/1,509,286 alleles · common exomes 164,943/1,360,478 · genomes 16,894/148,808 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	19.8%	5
Admixed American	12.8%	8
European (non-Finnish)	12.3%	8
Remaining individualsnot grpmax-eligible	12%	8
Amishnot grpmax-eligible	11.1%	9
Middle Eastern	11%	9
East Asian	8.97%	11
Finnishnot grpmax-eligible	7.48%	13
Ashkenazi Jewishnot grpmax-eligible	7.12%	14
African / African-American	6.4%	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.Ser332=
Coding: c.996T>C
MANE Select: NM_015166
dbSNP: rs11568187
Type: single nucleotide variant
Location: chr22:50064097 (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 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
MLC1 c.597+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-ser332 (accessed [today's date]).

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