Is CDKL5 p.Pro527Ser (c.1579C>T) pathogenic?

CDKL5 p.Pro527Ser (c.1579C>T) is classified Likely benign in CDKL5 (ClinVar, Expert panel, 3 submitters; last evaluated 2023-02-20). AlphaMissense: likely benign (0.1141); Very rare (popmax 0.00351%, afr); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Pro527Ser (c.1579C>T)?

CDKL5 p.Pro527Ser (c.1579C>T) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Pro527Ser (c.1579C>T) in the general population?

CDKL5 p.Pro527Ser (c.1579C>T) is very rare (popmax 0.00351%, afr) (gnomAD).

What do computational predictors say about CDKL5 p.Pro527Ser (c.1579C>T)?

AlphaMissense predicts likely benign (score 0.1141) — an in-silico prediction, not a clinical call.

CDKL5 p.Pro527Ser

c.1579C>T · rs1275389347 · VCV590134

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BS1 BS2_Supporting

Curation rationale (ClinGen, verbatim)

The allele frequency of the p.Pro527Ser variant in CDKL5 is 0.017% in African sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro527Ser variant is observed in at least 1 unaffected individual (internal database - Invitae) (BS2_supporting). In summary, the p.Pro527Ser variant in CDKL5 is classified as a Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting).

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

Computational evidence

Protein change
AlphaMissense	0.1141	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -6.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	24.5	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 0.00351% African / African-American · 2/57,050 alleles

Filtering AF 0.00081% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000624%

Overall 0.00124% 15/1,209,798 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00351%	28,525
European (non-Finnish)	0.00145%	68,859

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.Pro527Ser
Coding: c.1579C>T
MANE Select: NM_001323289
dbSNP: rs1275389347
Type: single nucleotide variant
Location: chrX:18604503 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 527: the 'disordered' region

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.Pro527Leu Likely benign ★★ 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-pro527ser (accessed [today's date]).

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