Is DCX p.Pro278Ala (c.832C>G) pathogenic?

DCX p.Pro278Ala (c.832C>G) is classified Uncertain significance in DCX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely benign (0.0531); Very rare (popmax 0.00656%, amr); Associated with lissencephaly type 1 due to doublecortin gene mutation.

What condition is associated with DCX p.Pro278Ala (c.832C>G)?

DCX p.Pro278Ala (c.832C>G) is associated with lissencephaly type 1 due to doublecortin gene mutation (ClinVar).

How common is DCX p.Pro278Ala (c.832C>G) in the general population?

DCX p.Pro278Ala (c.832C>G) is very rare (popmax 0.00656%, amr) (gnomAD).

What do computational predictors say about DCX p.Pro278Ala (c.832C>G)?

AlphaMissense predicts likely benign (score 0.0531) — an in-silico prediction, not a clinical call.

DCX p.Pro278Ala

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.832C>G · rs761180789 · VCV1705541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0531 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00656%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lissencephaly type 1 due to doublecortin gene mutation

Computational evidence

Protein change
AlphaMissense	0.0531	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 31 kb · p 0.075 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00656% Admixed American · 3/45,760 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000882%

Overall 0.000248% 3/1,209,950 alleles · very 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.Pro278Ala
Coding: c.832C>G
MANE Select: NM_001195553
dbSNP: rs761180789
Type: single nucleotide variant
Location: chrX:111331018 (GRCh38)
Structure: AlphaFold pLDDT 67.19 · 14 PDB
Residue 278: the 'disordered' region

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 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
DCX p.Arg303Ter 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-pro278ala (accessed [today's date]).

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