CDKL5 p.Leu97=
c.291C>T · rs138125282 · VCV748686
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Benign for CDKL5 disorder. Applied ACMG criteria (verbatim):
BS2 BS1 BP7
Curation rationale (ClinGen, verbatim)
The allele frequency of the p.Leu97= variant in CDKL5 is 0.011% in African sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Leu97= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Leu97= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). The p.Leu97= variant in CDKL5 has been reported apparently homozygous in an individual with infantile epileptic encephalopathy (PMID 28454995); no criteria were applied for this case. In summary, the p.Leu97= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP7).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.71 | GERP -4, phastCons 1 |
| Overall | ||
| CADD | 2.626 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0459% | 2,177 |
| African / African-American | 0.0158% | 6,331 |
| Remaining individualsnot grpmax-eligible | 0.00211% | 47,412 |
| European (non-Finnish) | 0.000224% | 445,692 |
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.Leu97=
- Coding
- c.291C>T
- MANE Select
- NM_001323289
- dbSNP
- rs138125282
- Type
- single nucleotide variant
- Location
- chrX:18579856 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 97
- the protein kinase domain; an α-helix
Similar variants
- CDKL5 p.Leu97Pro Likely pathogenic ★★★ 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-leu97 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown