Is CDKL5 p.Arg65Pro (c.194G>C) pathogenic?

CDKL5 p.Arg65Pro (c.194G>C) is classified Pathogenic in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with Angelman syndrome-like.

What condition is associated with CDKL5 p.Arg65Pro (c.194G>C)?

CDKL5 p.Arg65Pro (c.194G>C) is associated with Angelman syndrome-like, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Arg65Pro (c.194G>C) in the general population?

CDKL5 p.Arg65Pro (c.194G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Arg65Pro (c.194G>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

CDKL5 p.Arg65Pro

c.194G>C · rs267608436 · VCV1072615

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Angelman syndrome-like

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 4% in CDKL5
REVEL	0.76	pathogenic-leaning
SaProt	LLR -16.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKL5
Protein: p.Arg65Pro
Coding: c.194G>C
MANE Select: NM_001323289
dbSNP: rs267608436
Type: single nucleotide variant
Location: chrX:18575402 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 65: the protein kinase domain; an α-helix

Full CDKL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Angelman syndrome-like — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 2

Similar variants

CDKL5 p.Arg65Gln Likely benign ★★★ ⚠ same residue
RS1 p.Tyr65His Likely pathogenic ★ ⚠ same residue
RS1 p.Tyr65Ter Likely pathogenic ★ same residue
RS1 p.Tyr65Cys 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

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-arg65pro (accessed [today's date]).

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