CDKL5 p.Glu416fs
c.1247_1248del · rs786204967 · VCV189554
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Pathogenic for CDKL5 disorder. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PM6_Strong PS4
Curation rationale (ClinGen, verbatim)
The p.Glu416Valfs variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu416Valfs variant has been observed in at least 5 individuals with CDKL5 disease (PMID: 27779742, 27864847, 23064044, ClinVar Variation ID 189554) (PS4). The p.XX variant in GENE has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with CDKL5 disorder (PMID XX) (PMID 27779742, 27864847) (PM6_strong). This variant is absent from gnomAD (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria applied (PVS1, PS4, PM6_strong, PM2_supporting).
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. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 12 of 18 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 7.7 | GERP 2.4, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- CDKL5
- Protein
- p.Glu416fs
- Coding
- c.1247_1248del
- MANE Select
- NM_001323289
- dbSNP
- rs786204967
- Type
- Microsatellite
- Location
- chrX:18604169 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 416
- the 'disordered' region
Similar variants
- CDKL5 p.Glu416Ter Pathogenic ★ same residue
- CDKL5 p.Leu405fs Pathogenic ★★★ same condition
- CDKL5 p.Cys152_Asp153delinsTer Pathogenic/Likely pathogenic ★★ same condition
- CDKL5 p.Glu77fs Pathogenic ★★ same condition
- CDKL5 p.His690_Ser691insTer Pathogenic ★★ same condition
- CDKL5 p.Leu67fs Pathogenic ★★ same condition
- CDKL5 p.Lys776fs Pathogenic ★★ same condition
- CDKL5 p.Thr169fs 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-glu416fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown