Is CDKL5 p.His145fs (c.433del) pathogenic?

CDKL5 p.His145fs (c.433del) is classified Likely pathogenic in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). Associated with Rett syndrome.

What condition is associated with CDKL5 p.His145fs (c.433del)?

CDKL5 p.His145fs (c.433del) is associated with Rett syndrome (ClinVar).

How is Rett syndrome inherited?

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

CDKL5 p.His145fs

c.433del · VCV3602026

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Rett syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: CDKL5
Protein: p.His145fs
Coding: c.433del
MANE Select: NM_001323289
Type: Deletion
Location: chrX:18581919 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 145: the protein kinase domain; a UniProt-annotated variant site (in dee2; uncertain significance)

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

Disease context

Rett syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rett syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RS1 p.Asp145Asn Uncertain significance ★★★ ⚠ same residue
CDKL5 p.Leu58fs Pathogenic ★★ same condition
CDKL5 c.146-814_282+981del Likely pathogenic ★ same condition
CDKL5 p.His145Arg Uncertain significance ★ same residue
CDKL5 p.His145Tyr Uncertain significance ★ ⚠ same residue
RS1 p.Asp145= Likely benign ★ same residue
CDKL5 p.Ile72Thr Pathogenic ★★★ same condition
CDKL5 p.Leu67Phe Uncertain significance ★★★ ⚠ 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-his145fs (accessed [today's date]).

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