CDKL5 p.Glu203Asp
c.609G>C · rs2518857363 · VCV2925658
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Uncertain Significance for CDKL5 disorder. Applied ACMG criteria (verbatim):
PM6 PM2_Supporting PM5
Curation rationale (ClinGen, verbatim)
The p.Glu203Asp variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The p.Glu203Asp variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disorder (PMID 19362436) (PM6). A pathogenic missense variant (p.Glu203Gly) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (ClinVar, internal database - Labcorp Genetics) (PM5). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Glu203Asp variant in CDKL5 is classified as VUS based on the ACMG/AMP criteria (PM2_Supporting, PM6, PM5). (CDKL5 Specifications v.4.1; curation approved on 06/25/2025)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9997 | likely pathogenic · top 4% in CDKL5 |
|---|---|---|
| REVEL | 0.547 | indeterminate |
| SaProt | LLR -14.87 | 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 1.8 | GERP 0.74, phastCons 1 |
| Regional constraint | o/e 0.35 | constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic |
| Overall | ||
| CADD | 24.1 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Glu203Asp
- Coding
- c.609G>C
- MANE Select
- NM_001323289
- dbSNP
- rs2518857363
- Type
- single nucleotide variant
- Location
- chrX:18588008 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 203
- the protein kinase domain; an α-helix
Similar variants
- CDKL5 p.Glu203Gly Likely pathogenic ★ same residue
- CDKL5 p.Glu203Ter Pathogenic ★ same residue
- CDKL5 p.Glu203Lys Uncertain significance ★ ⚠ same residue
- CDKL5 p.Glu203fs Likely pathogenic ★ same residue
- RS1 p.Pro203Leu Pathogenic/Likely pathogenic ★★ same residue
- RS1 p.Pro203Ser Pathogenic ★ same residue
- RS1 p.Pro203Thr Pathogenic ★ same residue
- CDKL5 c.146-1G>A 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-glu203asp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown