CDKL5 p.Val718Met
c.2152G>A · rs267608653 · VCV143796
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Pathogenic for CDKL5 disorder. Applied ACMG criteria (verbatim):
PM2_Supporting PM6_Strong PS3_Supporting PS4 PP4
Curation rationale (ClinGen, verbatim)
The p.Val718Met variant in CDKL5 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with a CDKL5-related disorder (PMID 18790821, 27599155) (PM6_strong). The p.Val718Met variant has been observed at least 5 individuals with CDKL5-related disorders (PMID 31313283, 18790821, 27599155, GeneDx internal database) (PS4), including in an individual with a clinical phenotype very specific to a CDKL5-related disorder (PMID 27599155) (PP4). Additionally, an in vitro study using a minigene splicing assay showed that splicing is disrupted, resulting in exon 14 being omitted from the transcript (PMID: 29264392) (PS3_supporting). The p.Val718Met variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Val718Met variant in CDKL5 is classified as pathogenic for CDKL5-related disorders based on the ACMG/AMP criteria (PM6_strong, PS4, PP4, PS3_supporting, 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 | 0.9418 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.625 | indeterminate |
| SaProt | LLR -7.45 | tolerated |
| ⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | Δ0.32 | donor loss · deltas |
| Pangolin | Δ0.24 | loss · gain 0.04 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 0.70 | unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic |
| Overall | ||
| CADD | 33.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- CDKL5
- Protein
- p.Val718Met
- Coding
- c.2152G>A
- MANE Select
- NM_001323289
- dbSNP
- rs267608653
- Type
- single nucleotide variant
- Location
- chrX:18609570 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 718
- the 'disordered' region; a UniProt-annotated variant site (in dee2)
Similar variants
- 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
- 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-val718met (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown