Is MLC1 p.Leu135Pro (c.404T>C) pathogenic?

MLC1 p.Leu135Pro (c.404T>C) is classified Uncertain significance in MLC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-05). AlphaMissense: likely pathogenic (0.8005); Absent from gnomAD v4.1; Associated with megalencephalic leukoencephalopathy with subcortical cysts.

What condition is associated with MLC1 p.Leu135Pro (c.404T>C)?

MLC1 p.Leu135Pro (c.404T>C) is associated with megalencephalic leukoencephalopathy with subcortical cysts (ClinVar).

How common is MLC1 p.Leu135Pro (c.404T>C) in the general population?

MLC1 p.Leu135Pro (c.404T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLC1 p.Leu135Pro (c.404T>C)?

AlphaMissense predicts likely pathogenic (score 0.8005) — an in-silico prediction, not a clinical call.

MLC1 p.Leu135Pro

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.404T>C · rs1258044054 · VCV548492

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8005 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

megalencephalic leukoencephalopathy with subcortical cysts

Computational evidence

Protein change
AlphaMissense	0.8005	likely pathogenic
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 23 kb · p 0.13 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MLC1
Protein: p.Leu135Pro
Coding: c.404T>C
MANE Select: NM_015166
dbSNP: rs1258044054
Type: single nucleotide variant
Location: chr22:50079937 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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>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.597+1G>A Pathogenic/Likely pathogenic ★★ same condition
MLC1 c.597+2T>C Likely pathogenic ★★ same condition
MLC1 c.714+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-leu135pro (accessed [today's date]).

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