Is CDKL5 p.His467Arg (c.1400A>G) pathogenic?

CDKL5 p.His467Arg (c.1400A>G) is classified Benign/Likely benign in CDKL5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-07-01). AlphaMissense: likely pathogenic (0.6297); Very rare (popmax 0.00176%, sas); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.His467Arg (c.1400A>G)?

CDKL5 p.His467Arg (c.1400A>G) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.His467Arg (c.1400A>G) in the general population?

CDKL5 p.His467Arg (c.1400A>G) is very rare (popmax 0.00176%, sas) (gnomAD).

What do computational predictors say about CDKL5 p.His467Arg (c.1400A>G)?

AlphaMissense predicts likely pathogenic (score 0.6297) — an in-silico prediction, not a clinical call.

CDKL5 p.His467Arg

c.1400A>G · rs267608631 · VCV158178

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6297 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDKL5 disorder

Computational evidence

Protein change
AlphaMissense	0.6297	likely pathogenic
REVEL	0.401	indeterminate
SaProt	LLR -8.24	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	21.6	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 0.00176% South Asian · 1/56,946 alleles

Filtering AF 0.00066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000482%

Overall 0.00109% 12/1,097,196 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00176%	56,946
European (non-Finnish)	0.00123%	81,342

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.His467Arg
Coding: c.1400A>G
MANE Select: NM_001323289
dbSNP: rs267608631
Type: single nucleotide variant
Location: chrX:18604324 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 467: 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.His467Pro 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-his467arg (accessed [today's date]).

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