CDKL5 p.Ala334=
c.1002T>C · rs756986206 · VCV210642
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Benign for CDKL5 disorder. Applied ACMG criteria (verbatim):
BS2_Supporting BP7 BA1
Curation rationale (ClinGen, verbatim)
The allele frequency of the p.Ala334= variant in CDKL5 is 0.07448% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala334= variant is observed in at least 1 unaffected individual (Clinvar 210642) (BS2_supporting). The silent p.Ala334= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala334= variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BA2_supporting, BP7).
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. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.48 | GERP -0.063, phastCons 0.99 |
| Overall | ||
| CADD | 8.138 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.666% | 150 |
| South Asian | 0.0951% | 1,052 |
| Remaining individualsnot grpmax-eligible | 0.021% | 4,759 |
| African / African-American | 0.0105% | 9,530 |
| Admixed American | 0.00655% | 15,264 |
| European (non-Finnish) | 0.00224% | 44,718 |
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.Ala334=
- Coding
- c.1002T>C
- MANE Select
- NM_001323289
- dbSNP
- rs756986206
- Type
- single nucleotide variant
- Location
- chrX:18603926 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 334
- the 'disordered' region
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-ala334 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown