Is CDKL5 p.Thr562Ala (c.1684A>G) pathogenic?

CDKL5 p.Thr562Ala (c.1684A>G) is classified Likely benign in CDKL5 (ClinVar, Expert panel, 5 submitters; last evaluated 2025-02-28). AlphaMissense: likely benign (0.0594); Very rare (popmax 0.000447%, nfe); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Thr562Ala (c.1684A>G)?

CDKL5 p.Thr562Ala (c.1684A>G) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Thr562Ala (c.1684A>G) in the general population?

CDKL5 p.Thr562Ala (c.1684A>G) is very rare (popmax 0.000447%, nfe) (gnomAD).

What do computational predictors say about CDKL5 p.Thr562Ala (c.1684A>G)?

AlphaMissense predicts likely benign (score 0.0594) — an in-silico prediction, not a clinical call.

CDKL5 p.Thr562Ala

c.1684A>G · rs376341076 · VCV434666

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for CDKL5 disorder. Applied ACMG criteria (verbatim):

BS2 BP4

Curation rationale (ClinGen, verbatim)

The highest population minor allele frequency of the c.1684A>G (p.Thr562Ala) variant in CDKL5 in gnomAD v4.1 is 0.000004 in the European (Non-Finnish) population (not sufficient to meet BS1 criteria). The computational predictor REVEL gives a score of 0.133, evidence that does not predict a damaging effect on CDKL5 function (BP4). The p.Thr562Ala variant is observed in at least 2 unaffected individuals (Ambry Genetics: internal database, Labcorp Genetics Inc. (formerly Invitae): internal database) (BS2). In summary, the p.Thr562Ala variant in CDKL5 is classified as Likely Benign for CDKL5-associated disorder based on the ACMG/AMP criteria (BP4, BS2) (CDKL5 Specifications v.3.0; curation approved on 02/28/2025).

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

Computational evidence

Protein change
AlphaMissense	0.0594	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -6.40	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 2	GERP -0.094, phastCons 0.74
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	13.41	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

Grpmax group 0.000447% European (non-Finnish) · 4/895,326 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.00033% 4/1,210,493 alleles · very rare

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.Thr562Ala
Coding: c.1684A>G
MANE Select: NM_001323289
dbSNP: rs376341076
Type: single nucleotide variant
Location: chrX:18604608 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 562: the 'disordered' region

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.Thr562fs 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.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-thr562ala (accessed [today's date]).

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