Is CDKL5 p.Thr288Arg (c.863C>G) pathogenic?

CDKL5 p.Thr288Arg (c.863C>G) is classified Likely pathogenic in CDKL5 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.9849); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Thr288Arg (c.863C>G)?

CDKL5 p.Thr288Arg (c.863C>G) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Thr288Arg (c.863C>G) in the general population?

CDKL5 p.Thr288Arg (c.863C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Thr288Arg (c.863C>G)?

AlphaMissense predicts likely pathogenic (score 0.9849) — an in-silico prediction, not a clinical call.

CDKL5 p.Thr288Arg

c.863C>G · rs267606713 · VCV1879751

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9849 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Pathogenic for CDKL5 disorder. Applied ACMG criteria (verbatim):

PM2_Supporting PS4_Supporting PS2 PP3

Curation rationale (ClinGen, verbatim)

The p.Thr288Arg variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with early onset epilepsy (internal database - CeGaT Center for Human Genetics Tuebingen) (PS2). The p.Thr288Arg variant has been observed in at least 1 other individual with features of CDKL5 disorder (internal database - LabCorp (formerly Invitae)) (PS4_Supporting). The p.Thr288Arg variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Thr288Arg variant in CDKL5 is classified as Likely Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS2, PS4_Supporting, PM2_Supporting, PP3). (CDKL5 Specifications v5.0; curation approved on 10/28/2025)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9849	likely pathogenic ✓ concordant with ClinVar
REVEL	0.647	pathogenic-leaning
SaProt	LLR -12.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	24.6	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

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.Thr288Arg
Coding: c.863C>G
MANE Select: NM_001323289
dbSNP: rs267606713
Type: single nucleotide variant
Location: chrX:18598499 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 288: the protein kinase domain; a UniProt-annotated variant site (in dee2); an α-helix

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: developmental and epileptic encephalopathy, 2

Similar variants

CDKL5 p.Thr288Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-thr288arg (accessed [today's date]).

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