Is CDKL5 p.Asp422Glu (c.1266C>A) pathogenic?

CDKL5 p.Asp422Glu (c.1266C>A) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-09-12). AlphaMissense: likely benign (0.106); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Asp422Glu (c.1266C>A)?

CDKL5 p.Asp422Glu (c.1266C>A) is associated with CDKL5 disorder, atypical Rett syndrome (ClinVar).

How common is CDKL5 p.Asp422Glu (c.1266C>A) in the general population?

CDKL5 p.Asp422Glu (c.1266C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Asp422Glu (c.1266C>A)?

AlphaMissense predicts likely benign (score 0.106) — an in-silico prediction, not a clinical call.

CDKL5 p.Asp422Glu

c.1266C>A · rs762708691 · VCV189601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.106 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKL5 disorder

Computational evidence

Protein change
AlphaMissense	0.106	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -6.12	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 1.4	GERP -0.35, phastCons 0.92
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	14.75	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

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: CDKL5
Protein: p.Asp422Glu
Coding: c.1266C>A
MANE Select: NM_001323289
dbSNP: rs762708691
Type: single nucleotide variant
Location: chrX:18604190 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 422: the 'disordered' region

Full CDKL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CDKL5 disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atypical Rett syndrome

Similar variants

CDKL5 c.146-1G>A Pathogenic ★★★ same condition
CDKL5 p.Ala157Pro Likely pathogenic ★★★ same condition
CDKL5 p.Ala157Val Likely pathogenic ★★★ same condition
CDKL5 p.Ala40Val Pathogenic ★★★ same condition
CDKL5 p.Arg178Gln Pathogenic ★★★ same condition
CDKL5 p.Arg717= Likely pathogenic ★★★ same condition
CDKL5 p.Arg948Ter Pathogenic ★★★ same condition
CDKL5 p.Asn71Asp 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/cdkl5-p-asp422glu (accessed [today's date]).

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