Is CDKL5 p.Arg305His (c.914G>A) pathogenic?

CDKL5 p.Arg305His (c.914G>A) is classified Likely benign in CDKL5 (ClinVar, Expert panel, 3 submitters; last evaluated 2026-08-24). AlphaMissense: likely benign (0.3002); Very rare (popmax 0.00219%, amr); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Arg305His (c.914G>A)?

CDKL5 p.Arg305His (c.914G>A) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Arg305His (c.914G>A) in the general population?

CDKL5 p.Arg305His (c.914G>A) is very rare (popmax 0.00219%, amr) (gnomAD).

What do computational predictors say about CDKL5 p.Arg305His (c.914G>A)?

AlphaMissense predicts likely benign (score 0.3002) — an in-silico prediction, not a clinical call.

CDKL5 p.Arg305His

c.914G>A · rs767817521 · VCV1765968

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00219%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDKL5 disorder

Computational evidence

Protein change
AlphaMissense	0.3002	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	24.6	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 0.00219% Admixed American · 1/45,756 alleles

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

Overall 0.00058% 7/1,207,337 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00219%	45,756
Remaining individualsnot grpmax-eligible	0.0021%	47,508
African / African-American	0.00175%	57,093
European (non-Finnish)	0.000448%	223,194

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.Arg305His
Coding: c.914G>A
MANE Select: NM_001323289
dbSNP: rs767817521
Type: single nucleotide variant
Location: chrX:18598550 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 305: 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.Arg305= Benign/Likely benign ★★ same residue
CDKL5 p.Arg305Cys Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg305his (accessed [today's date]).

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