Is CDKL5 p.Ala40Thr (c.118G>A) pathogenic?

CDKL5 p.Ala40Thr (c.118G>A) is classified Pathogenic in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1.

How common is CDKL5 p.Ala40Thr (c.118G>A) in the general population?

CDKL5 p.Ala40Thr (c.118G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Ala40Thr (c.118G>A)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

CDKL5 p.Ala40Thr

c.118G>A · VCV4540006

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,130,622)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 4% in CDKL5
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -16.51	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,130,622). 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.Ala40Thr
Coding: c.118G>A
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18564495 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 40: the protein kinase domain; a UniProt-annotated variant site (in dee2; causes mislocalization of the protein in the cytoplasm); a β-strand

Full CDKL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKL5 p.Ala40Val Pathogenic ★★★ same residue
CDKL5 p.Ala40Glu Likely pathogenic ★ same residue
CDKL5 p.Ala40= Likely benign ★ same residue
CDKL5 c.146-1G>A Pathogenic ★★★ same type
CDKL5 p.Ala157Pro Likely pathogenic ★★★ same type
CDKL5 p.Ala157Val Likely pathogenic ★★★ same type
CDKL5 p.Arg178Gln Pathogenic ★★★ same type
CDKL5 p.Arg717= Likely pathogenic ★★★ same type

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-ala40thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown