CDKL5 p.Leu97Pro
c.290T>C · rs1925418549 · VCV870171
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Likely Pathogenic for CDKL5 disorder. Applied ACMG criteria (verbatim):
PM2_Supporting PS2 PP3
Curation rationale (ClinGen, verbatim)
The p.Leu97Pro variant in CDKL5 occurs in the de novo state (biological parentage confirmed) in an individual (GeneDx Internal Database) (PS2). The p.Leu97Pro variant in CDKL5 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu97Pro variant in CDKL5 is classified as likely pathogenic for a CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PM2_supporting, PP3).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9998 | likely pathogenic ✓ concordant with ClinVar · top 4% in CDKL5 |
|---|---|---|
| REVEL | 0.765 | pathogenic-leaning |
| SaProt | LLR -12.93 | 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 2.6, phastCons 1 |
| Regional constraint | o/e 0.35 | constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic |
| Overall | ||
| CADD | 27.2 | PHRED · no single calibrated threshold — expert panels disagree |
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.Leu97Pro
- Coding
- c.290T>C
- MANE Select
- NM_001323289
- dbSNP
- rs1925418549
- Type
- single nucleotide variant
- Location
- chrX:18579855 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 97
- the protein kinase domain; an α-helix
Similar variants
- CDKL5 p.Leu97= Benign ★★★ same residue
- RS1 p.Thr97Pro 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-leu97pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown