Is CDKL5 p.Ser815= (c.2445C>T) pathogenic?

CDKL5 p.Ser815= (c.2445C>T) is classified Benign in CDKL5 (ClinVar, Expert panel, 4 submitters; last evaluated 2021-03-26). Ultra-rare (popmax 0.0832%, afr); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Ser815= (c.2445C>T)?

CDKL5 p.Ser815= (c.2445C>T) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Ser815= (c.2445C>T) in the general population?

CDKL5 p.Ser815= (c.2445C>T) is ultra-rare (popmax 0.0832%, afr) (gnomAD).

CDKL5 p.Ser815=

c.2445C>T · rs371902632 · VCV258978

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0832%, afr)

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Benign for CDKL5 disorder. Applied ACMG criteria (verbatim):

BP7 BA1

Curation rationale (ClinGen, verbatim)

The allele frequency of the p.Ser815= variant in CDKL5 is 0.1% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Ser815= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ser815= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BP7).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.14, phastCons 1
Overall
CADD	8.281	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0832% African / African-American · 47/56,520 alleles

Filtering AF 0.0642% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0575%

Overall 0.00424% 51/1,204,226 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0832%	1,203
Admixed American	0.0044%	22,712
Remaining individualsnot grpmax-eligible	0.00421%	23,735

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.Ser815=
Coding: c.2445C>T
MANE Select: NM_001323289
dbSNP: rs371902632
Type: single nucleotide variant
Location: chrX:18625196 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 815: the 'disordered' region; a UniProt-annotated variant site (in dee2)

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.Ser815Ile 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-ser815 (accessed [today's date]).

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