Is CDKL5 p.Asn276Ser (c.827A>G) pathogenic?

CDKL5 p.Asn276Ser (c.827A>G) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-09). AlphaMissense: likely benign (0.1093); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Asn276Ser (c.827A>G)?

CDKL5 p.Asn276Ser (c.827A>G) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Asn276Ser (c.827A>G) in the general population?

CDKL5 p.Asn276Ser (c.827A>G) is absent from gnomAD v4.1 (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.Asn276Ser (c.827A>G)?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

CDKL5 p.Asn276Ser

c.827A>G · VCV3338396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,204,337)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 2

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -9.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.41	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	23.3	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

No allele count reported in gnomAD v4.1 (AN 1,204,337). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDKL5
Protein: p.Asn276Ser
Coding: c.827A>G
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18598463 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 276: 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 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.Asp193Gly 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-asn276ser (accessed [today's date]).

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