Is MLC1 p.Ser199= (c.597A>G) pathogenic?

MLC1 p.Ser199= (c.597A>G) is classified Benign in MLC1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 22.3%, sas) — too common for a highly-penetrant pathogenic allele; Associated with megalencephalic leukoencephalopathy with subcortical cysts 1.

What condition is associated with MLC1 p.Ser199= (c.597A>G)?

MLC1 p.Ser199= (c.597A>G) is associated with megalencephalic leukoencephalopathy with subcortical cysts 1, megalencephalic leukoencephalopathy with subcortical cysts (ClinVar).

MLC1 p.Ser199=

Q: How common is MLC1 p.Ser199= (c.597A>G) in the general population?

MLC1 p.Ser199= (c.597A>G) is common (popmax 22.3%, 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.597A>G · rs6010164 · VCV129615

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 22.3%, 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	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.7	GERP -2.9
Overall
CADD	0.024	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.3% South Asian · 20,265/91,040 alleles

Filtering AF 22% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.9%

Overall 12.8% 205,688/1,612,712 alleles · common exomes 188,041/1,460,548 · genomes 17,647/152,164 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	22.3%	4
Middle Eastern	13.8%	7
Admixed American	13.7%	7
Remaining individualsnot grpmax-eligible	12.7%	8
European (non-Finnish)	12.6%	8
Amishnot grpmax-eligible	11%	9
African / African-American	10.3%	10
East Asian	9.79%	10
Finnishnot grpmax-eligible	8.23%	12
Ashkenazi Jewishnot grpmax-eligible	6.34%	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.Ser199=
Coding: c.597A>G
MANE Select: NM_015166
dbSNP: rs6010164
Type: single nucleotide variant
Location: chr22:50076841 (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.Ser199Pro Uncertain significance ★★ ⚠ same residue
MLC1 p.Ser199Ter Likely pathogenic ★ same residue
MLC1 p.Ser199Leu Uncertain significance ★ ⚠ 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

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-ser199 (accessed [today's date]).

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