CDKL5 p.His124fs
c.372_385del · rs2518849265 · VCV2105592
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Pathogenic for CDKL5 disorder. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PS4_Supporting
Curation rationale (ClinGen, verbatim)
The p.His124GlnfsTer2 variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.His124GlnfsTer2 variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). The p.His124GlnfsTer2 variant has been observed in at least 2 individuals with CDKL5 disorder (PMID 38539105, internal database - Labcorp (formerly Invitae)) (PS4_Supporting). In summary, the p.His124GlnfsTer2 variant in CDKL5 is classified as pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM2_Supporting, PS4_Supporting). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025)
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 6 of 18 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | 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.His124fs
- Coding
- c.372_385del
- MANE Select
- NM_001323289
- dbSNP
- rs2518849265
- Type
- Deletion
- Location
- chrX:18579936 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 124
- the protein kinase domain; an α-helix
Similar variants
- RS1 p.Gln124fs Pathogenic same residue
- CDKL5 p.Tyr941fs Pathogenic ★★★ same condition
- CDKL5 p.Lys432_Tyr433delinsAsn Uncertain significance ★★★ same condition
- CDKL5 p.Ala486_Lys487del Benign ★★★ same condition
- CDKL5 p.Ala372fs Pathogenic ★★ same condition
- CDKL5 p.Ala811fs Pathogenic ★★ same condition
- CDKL5 p.Arg781fs Pathogenic ★★ same condition
- CDKL5 p.Arg943fs 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-his124fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown