CDKL5 p.Val172Ile
c.514G>A · rs797044858 · VCV208653
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Uncertain Significance for CDKL5 disorder. Applied ACMG criteria (verbatim):
PM6 PM2_Supporting
Curation rationale (ClinGen, verbatim)
The p.Val172Ile variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with early onset epileptic encephalopathy (PMID 25356970) (PM6). The p.Val172Ile variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Val172Ile variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM6, PM2_supporting). (CDKL5 Specifications v.4.1; curation approved on [5/7/2025])
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9157 | likely pathogenic |
|---|---|---|
| REVEL | 0.391 | indeterminate |
| SaProt | LLR -11.00 | damaging |
| ⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.4, phastCons 1 |
| Regional constraint | o/e 0.35 | constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic |
| Overall | ||
| CADD | 26.6 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Val172Ile
- Coding
- c.514G>A
- MANE Select
- NM_001323289
- dbSNP
- rs797044858
- Type
- single nucleotide variant
- Location
- chrX:18584313 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 172
- the protein kinase domain; an α-helix
Similar variants
- CDKL5 p.Val172Gly Pathogenic ★ same residue
- RS1 p.Asn172Asp 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-val172ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown