Is CDKL5 p.Thr296Ala (c.886A>G) pathogenic?

CDKL5 p.Thr296Ala (c.886A>G) is classified Benign/Likely benign in CDKL5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0502); Very rare (popmax 0.00281%, nfe); Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Thr296Ala (c.886A>G)?

CDKL5 p.Thr296Ala (c.886A>G) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Thr296Ala (c.886A>G) in the general population?

CDKL5 p.Thr296Ala (c.886A>G) is very rare (popmax 0.00281%, nfe) (gnomAD).

How is CDKL5-deficiency disorder inherited?

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

What do computational predictors say about CDKL5 p.Thr296Ala (c.886A>G)?

AlphaMissense predicts likely benign (score 0.0502) — an in-silico prediction, not a clinical call.

CDKL5 p.Thr296Ala

c.886A>G · rs751995225 · VCV383412

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0502 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00281%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 2

Computational evidence

Protein change
AlphaMissense	0.0502	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -2.69	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 4.9	GERP -0.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	13.17	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

Grpmax group 0.00281% European (non-Finnish) · 25/888,908 alleles

Filtering AF 0.00193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00163%

Overall 0.00241% 29/1,203,272 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00281%	35,556
Finnishnot grpmax-eligible	0.00214%	46,640
Remaining individualsnot grpmax-eligible	0.00211%	47,367
South Asian	0.00176%	56,691
African / African-American	0.00175%	57,099

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: CDKL5
Protein: p.Thr296Ala
Coding: c.886A>G
MANE Select: NM_001323289
dbSNP: rs751995225
Type: single nucleotide variant
Location: chrX:18598522 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 296: the protein kinase domain; an α-helix

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

Disease context

developmental and epileptic encephalopathy, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CDKL5-deficiency disorder (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

CDKL5 p.Thr296Lys Uncertain significance ★ ⚠ 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-thr296ala (accessed [today's date]).

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