Is CDKL5 p.Ala40Val (c.119C>T) pathogenic?

CDKL5 p.Ala40Val (c.119C>T) is classified Pathogenic in CDKL5 (ClinVar, Expert panel, 8 submitters; last evaluated 2021-03-30). AlphaMissense: likely pathogenic (0.9983); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Ala40Val (c.119C>T)?

CDKL5 p.Ala40Val (c.119C>T) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2, atypical Rett syndrome (ClinVar).

How common is CDKL5 p.Ala40Val (c.119C>T) in the general population?

CDKL5 p.Ala40Val (c.119C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Ala40Val (c.119C>T)?

AlphaMissense predicts likely pathogenic (score 0.9983) — an in-silico prediction, not a clinical call.

CDKL5 p.Ala40Val

c.119C>T · rs122460159 · VCV11502

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9983 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,116,332)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Pathogenic for CDKL5 disorder. Applied ACMG criteria (verbatim):

PS2_VeryStrong PM2_Supporting PS4_strong PM1 PP3

Curation rationale (ClinGen, verbatim)

The p.Ala40Val variant in CDKL5 has been reported in at least 4 unconfirmed de novo occurrences in patients with CDKL5 disorder (PMID 27779742, 17993579, 22678952, 19793311) (PM6_VS). It is also reported in the mosaic state in a male patient with CDKL5 disorder (PMID 25819767) and therefore confirmed to be de novo (PS2). The p.Ala40Val variant has been observed in at least 10 other individuals with CDKL5 disorder (27779742, 25819767, 17993579, 22678952, 19793311, 21309761, 19780792) (PS4). The variant is absent in gnomAD (PM2_supporting). The variant is located in a well-characterized (ATP binding region: aa 19-43) functional domain of CDKL5 (PMID: 28544139, 17993579, 23064044, 29264392) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Ala40Val in CDKL5 is classified as Pathogenic based on the ACMG/AMP criteria (PM6_very strong, PS2, PS4_strong, PM1, PM2_supporting, PP3).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9983	likely pathogenic ✓ concordant with ClinVar · top 7% in CDKL5
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -15.90	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 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	28.4	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 1,116,332). 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.Ala40Val
Coding: c.119C>T
MANE Select: NM_001323289
dbSNP: rs122460159
Type: single nucleotide variant
Location: chrX:18564496 (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

Disease context

CDKL5 disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 2 atypical Rett syndrome

Similar variants

CDKL5 p.Ala40Glu Likely pathogenic ★ same residue
CDKL5 p.Ala40= Likely benign ★ same residue
CDKL5 p.Ala40Thr Pathogenic ★ 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.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-ala40val (accessed [today's date]).

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