Is MLC1 p.Leu306Gln (c.917T>A) pathogenic?

MLC1 p.Leu306Gln (c.917T>A) is classified Conflicting classifications of pathogenicity in MLC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.6355); Very rare (popmax 0.00017%, nfe); Associated with megalencephalic leukoencephalopathy with subcortical cysts 1.

What condition is associated with MLC1 p.Leu306Gln (c.917T>A)?

MLC1 p.Leu306Gln (c.917T>A) is associated with megalencephalic leukoencephalopathy with subcortical cysts 1 (ClinVar).

How common is MLC1 p.Leu306Gln (c.917T>A) in the general population?

MLC1 p.Leu306Gln (c.917T>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MLC1 p.Leu306Gln (c.917T>A)?

AlphaMissense predicts likely pathogenic (score 0.6355) — an in-silico prediction, not a clinical call.

MLC1 p.Leu306Gln

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.917T>A · rs768711345 · VCV800515

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

megalencephalic leukoencephalopathy with subcortical cysts 1

Computational evidence

Protein change
AlphaMissense	0.6355	likely pathogenic
REVEL	0.673	pathogenic-leaning
SaProt	LLR -10.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 0.09, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 23 kb · p 0.13 · regional, not allelic
Overall
CADD	22.1	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,134 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,603,126 alleles · very rare exomes 2/1,450,804 · genomes 0/152,322 · joint denominator

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.Leu306Gln
Coding: c.917T>A
MANE Select: NM_015166
dbSNP: rs768711345
Type: single nucleotide variant
Location: chr22:50064176 (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

For Megalencephalic leukoencephalopathy with subcortical cysts (Orphanet):

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

Similar variants

MLC1 p.Leu306Arg 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
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-leu306gln (accessed [today's date]).

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