Is DCX p.Val136Leu (c.406G>C) pathogenic?

DCX p.Val136Leu (c.406G>C) is classified Uncertain significance in DCX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-12). AlphaMissense: ambiguous (0.5523); Ultra-rare (popmax 0.0106%, sas); Associated with lissencephaly type 1 due to doublecortin gene mutation.

What condition is associated with DCX p.Val136Leu (c.406G>C)?

DCX p.Val136Leu (c.406G>C) is associated with lissencephaly type 1 due to doublecortin gene mutation (ClinVar).

How common is DCX p.Val136Leu (c.406G>C) in the general population?

DCX p.Val136Leu (c.406G>C) is ultra-rare (popmax 0.0106%, sas) (gnomAD).

What do computational predictors say about DCX p.Val136Leu (c.406G>C)?

AlphaMissense predicts ambiguous (score 0.5523) — an in-silico prediction, not a clinical call.

DCX p.Val136Leu

Q: How is Lissencephaly type 1 due to doublecortin gene mutation inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.406G>C · VCV3370610

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5523 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

lissencephaly type 1 due to doublecortin gene mutation

Computational evidence

Protein change
AlphaMissense	0.5523	ambiguous
REVEL	0.198	benign-leaning
SaProt	LLR -7.77	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -0.94, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 77 kb · p 4.4e-24 · regional, not allelic
Overall
CADD	20.1	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 0.0106% South Asian · 6/56,788 alleles

Filtering AF 0.00459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.000496% 6/1,210,058 alleles · ultra-rare

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: DCX
Protein: p.Val136Leu
Coding: c.406G>C
MANE Select: NM_001195553
Type: single nucleotide variant
Location: chrX:111401289 (GRCh38)
Structure: AlphaFold pLDDT 67.19 · 14 PDB
Residue 136: the doublecortin 1 domain

Full DCX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lissencephaly type 1 due to doublecortin gene mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lissencephaly type 1 due to doublecortin gene mutation (Orphanet):

Inheritance: X-linked recessive
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

DCX p.Val136Met Uncertain significance ★ ⚠ same residue
DCX c.809-1G>A Pathogenic/Likely pathogenic ★★ same condition
DCX p.Arg178Cys Pathogenic/Likely pathogenic ★★ same condition
DCX p.Arg186Leu Pathogenic/Likely pathogenic ★★ same condition
DCX p.Arg192Trp Pathogenic/Likely pathogenic ★★ same condition
DCX p.Arg196Cys Pathogenic ★★ same condition
DCX p.Arg196His Pathogenic/Likely pathogenic ★★ same condition
DCX p.Arg272Ter 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/dcx-p-val136leu (accessed [today's date]).

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