Is CDKL5 p.Arg175Ser (c.525A>T) pathogenic?

CDKL5 p.Arg175Ser (c.525A>T) is classified Likely pathogenic in CDKL5 (ClinVar, Single submitter, 3 submitters; last evaluated 2024-09-23). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Arg175Ser (c.525A>T)?

CDKL5 p.Arg175Ser (c.525A>T) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2, atypical Rett syndrome (ClinVar).

How common is CDKL5 p.Arg175Ser (c.525A>T) in the general population?

CDKL5 p.Arg175Ser (c.525A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Arg175Ser (c.525A>T)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

CDKL5 p.Arg175Ser

c.525A>T · rs61749700 · VCV11497

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDKL5 disorder

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 4% in CDKL5
REVEL	0.611	indeterminate
SaProt	LLR -15.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -4.7, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKL5
Protein: p.Arg175Ser
Coding: c.525A>T
MANE Select: NM_001323289
dbSNP: rs61749700
Type: single nucleotide variant
Location: chrX:18584324 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 175: the protein kinase domain; a UniProt-annotated variant site (in dee2; affect activity; does not affect the cellular distribution of the protein); an α-helix

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 atypical Rett syndrome

Similar variants

CDKL5 p.Arg175Gly Pathogenic ★ same residue
CDKL5 p.Arg175Lys Likely pathogenic ★ same residue
CDKL5 p.Arg175Thr Likely pathogenic ★ same residue
CDKL5 p.Arg175Ile Likely pathogenic ★ same residue
RS1 p.Val175= 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

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-arg175ser (accessed [today's date]).

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