CDKL5 p.Ala157Val
c.470C>T · rs863225066 · VCV217360
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Likely Pathogenic for CDKL5 disorder. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Supporting PS2 PP3 PM5
Curation rationale (ClinGen, verbatim)
The p.Ala157Val variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with infantile epilepsy (GeneDx Internal Database) (PS2). The p.Ala157Val 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). The p.Ala157Val variant has been observed in individuals reported to have Rett syndrome or CDKL5 Deficiency disorder, however, additional clinical and segregation information was not provided (PMID: 32472944; 31313283) (PS4_supporting_met, PP4_not met). A pathogenic missense variant (p.Ala157Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (Invitae internal database). In summary, the p.Ala157Val variant in CDKL5 is classified as likely pathogenic for CDKL5-related disorder based on the ACMG/AMP criteria (PS2, PP3, PM2_supporting, PS4_supporting,PM5).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9995 | likely pathogenic ✓ concordant with ClinVar · top 4% in CDKL5 |
|---|---|---|
| REVEL | 0.787 | moderately pathogenic-leaning |
| SaProt | LLR -12.17 | 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 7.7 | GERP 2.4, 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
No allele count reported in gnomAD v4.1 (AN 1,197,831). 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.Ala157Val
- Coding
- c.470C>T
- MANE Select
- NM_001323289
- dbSNP
- rs863225066
- Type
- single nucleotide variant
- Location
- chrX:18584269 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 157
- the protein kinase domain
Similar variants
- CDKL5 p.Ala157Pro Likely pathogenic ★★★ same residue
- RS1 p.Thr157= Likely benign ★ same residue
- CDKL5 c.146-1G>A Pathogenic ★★★ same condition
- CDKL5 p.Ala40Val Pathogenic ★★★ same condition
- CDKL5 p.Arg178Gln Pathogenic ★★★ same condition
- CDKL5 p.Arg717= Likely pathogenic ★★★ same condition
- CDKL5 p.Arg948Ter Pathogenic ★★★ same condition
- CDKL5 p.Asn71Asp 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-ala157val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown