Is CDKL5 p.Cys199Arg (c.595T>C) pathogenic?

CDKL5 p.Cys199Arg (c.595T>C) is classified Conflicting classifications of pathogenicity in CDKL5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-05). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Cys199Arg (c.595T>C)?

CDKL5 p.Cys199Arg (c.595T>C) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Cys199Arg (c.595T>C) in the general population?

CDKL5 p.Cys199Arg (c.595T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Cys199Arg (c.595T>C)?

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

CDKL5 p.Cys199Arg

c.595T>C · rs2518857335 · VCV1803089

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKL5 disorder

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 4% in CDKL5
REVEL	0.696	pathogenic-leaning
SaProt	LLR -15.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	29.0	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.Cys199Arg
Coding: c.595T>C
MANE Select: NM_001323289
dbSNP: rs2518857335
Type: single nucleotide variant
Location: chrX:18587994 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 199: the protein kinase domain; 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

Similar variants

RS1 p.Ile199Thr Pathogenic ★★ same residue
RS1 p.Ile199= Benign/Likely benign ★★ same residue
CDKL5 p.Cys199= 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

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-cys199arg (accessed [today's date]).

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