Is CDKL5 p.Arg822His (c.2465G>A) pathogenic?

CDKL5 p.Arg822His (c.2465G>A) is classified Likely benign in CDKL5 (ClinVar, Expert panel, 7 submitters; last evaluated 2023-02-20). AlphaMissense: likely benign (0.0828); Very rare (popmax 0.00201%, nfe); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Arg822His (c.2465G>A)?

CDKL5 p.Arg822His (c.2465G>A) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Arg822His (c.2465G>A) in the general population?

CDKL5 p.Arg822His (c.2465G>A) is very rare (popmax 0.00201%, nfe) (gnomAD).

What do computational predictors say about CDKL5 p.Arg822His (c.2465G>A)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

CDKL5 p.Arg822His

c.2465G>A · rs376429571 · VCV377094

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00201%, 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 p.Arg822His variant in CDKL5 is present in 3 XX and 1 XY individuals in gnomAD v3.1.2 (0.0076%) (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Arg822His variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Arg822His variant is observed in at least 2 unaffected individuals (internal database-GeneDX) (BS2). In summary, the p.Arg822His variant in CDKL5 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP4).

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

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -6.49	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 10	GERP 2.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	20.4	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

Grpmax group 0.00201% European (non-Finnish) · 18/893,367 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 18/1,205,205 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.Arg822His
Coding: c.2465G>A
MANE Select: NM_001323289
dbSNP: rs376429571
Type: single nucleotide variant
Location: chrX:18625216 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 822: 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.Arg822Cys Uncertain significance ★★ ⚠ same residue
CDKL5 p.Arg822= Benign/Likely benign ★★ same residue
CDKL5 p.Arg822fs 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

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-arg822his (accessed [today's date]).

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