Is CDKL5 p.Tyr86fs (c.255dup) pathogenic?

CDKL5 p.Tyr86fs (c.255dup) is classified Likely pathogenic in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-30). Associated with Rett syndrome.

What condition is associated with CDKL5 p.Tyr86fs (c.255dup)?

CDKL5 p.Tyr86fs (c.255dup) 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.Tyr86fs

c.255dup · VCV3602052

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 5 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1

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

Variant & gene context

Gene: CDKL5
Protein: p.Tyr86fs
Coding: c.255dup
MANE Select: NM_001323289
Type: Duplication
Location: chrX:18575462 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 86: the protein kinase domain; a β-strand

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

CDKL5 p.Asn95fs Pathogenic ★ same condition
CDKL5 p.Leu653fs Likely pathogenic ★ same condition
CDKL5 p.Ser745Ter Likely pathogenic ★ same condition
CDKL5 p.Thr531fs Likely pathogenic ★ same condition
CDKL5 p.Tyr86Asp Likely pathogenic ★ same residue
CDKL5 p.Tyr86Ter Pathogenic ★ same residue
RS1 p.Pro86Leu Uncertain significance ★ ⚠ same residue
RS1 p.Pro86= Likely benign ★ same residue

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-tyr86fs (accessed [today's date]).

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