Is CDKL5 p.Pro852= (c.2556G>A) pathogenic?

CDKL5 p.Pro852= (c.2556G>A) is classified Likely benign in CDKL5 (ClinVar, Expert panel, 3 submitters; last evaluated 2023-06-15). Ultra-rare (popmax 0.046%, mid); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Pro852= (c.2556G>A)?

CDKL5 p.Pro852= (c.2556G>A) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Pro852= (c.2556G>A) in the general population?

CDKL5 p.Pro852= (c.2556G>A) is ultra-rare (popmax 0.046%, mid) (gnomAD).

CDKL5 p.Pro852=

c.2556G>A · rs748905018 · VCV1046637

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.046%, mid)

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BP7 BP4

Curation rationale (ClinGen, verbatim)

The c.2556G>A p.Pro852= variant in CDKL5 (NM_001323289.2) is present in 2 female individuals in gnomAD (0.0072%) (not sufficient to meet BS1 criteria). The silent p.Pro852= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the p.Pro852= variant in CDKL5 is classified as Likely Benign based on the ACMG/AMP criteria (BP4, 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 -1.6	GERP -4.4
Overall
CADD	0.345	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.046% Middle Eastern · 2/4,348 alleles

Filtering AF 0.00813% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00373%

Overall 0.00109% 12/1,097,829 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.046%	2,174
East Asian	0.0148%	6,763
South Asian	0.00175%	56,998
European (non-Finnish)	0.000447%	223,780

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.Pro852=
Coding: c.2556G>A
MANE Select: NM_001323289
dbSNP: rs748905018
Type: single nucleotide variant
Location: chrX:18628430 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 852: 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.Pro852Leu Benign ★★★ same residue
CDKL5 p.Pro852Arg 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

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-pro852 (accessed [today's date]).

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