Is CDKL5 p.Val732Met (c.2194G>A) pathogenic?

CDKL5 p.Val732Met (c.2194G>A) is classified Uncertain significance in CDKL5 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1303); Very rare (popmax 0.00178%, sas); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Val732Met (c.2194G>A)?

CDKL5 p.Val732Met (c.2194G>A) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Val732Met (c.2194G>A) in the general population?

CDKL5 p.Val732Met (c.2194G>A) is very rare (popmax 0.00178%, sas) (gnomAD).

What do computational predictors say about CDKL5 p.Val732Met (c.2194G>A)?

AlphaMissense predicts likely benign (score 0.1303) — an in-silico prediction, not a clinical call.

CDKL5 p.Val732Met

c.2194G>A · rs888325600 · VCV1648546

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1303 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Uncertain Significance for CDKL5 disorder. Applied ACMG criteria (verbatim):

BP4

Curation rationale (ClinGen, verbatim)

The highest population minor allele frequency of the p.Val732Met variant in CDKL5 in gnomAD v4.1 is 0.00002163 in the "remaining" population (not sufficient to meet BS1 criteria). The computational predictor REVEL gives a 0.276 of p.Val732Met, which is below the threshold of 0.29. The splice site predictor, SpliceAI, indicated that the variant has no impact on splicing. Based on this evidence, p.Val732Met does not predict a damaging effect on CDKL5 function (BP4). The p.Val732Met variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Val732Met variant in CDKL5 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BP4). (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	0.1303	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% South Asian · 1/56,271 alleles

Filtering AF 0.000728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000575%

Overall 0.00118% 14/1,185,261 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00216%	46,238
South Asiangrpmax	0.00178%	56,271
European (non-Finnish)	0.00136%	73,283

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val732Met
Coding: c.2194G>A
MANE Select: NM_001323289
dbSNP: rs888325600
Type: single nucleotide variant
Location: chrX:18613193 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 732: the 'disordered' region; a UniProt-annotated variant site (in dee2)

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

Similar variants

CDKL5 p.Val732Glu 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
CDKL5 p.Arg948Ter 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-val732met (accessed [today's date]).

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