Is CDKL5 p.His145Arg (c.434A>G) pathogenic?

CDKL5 p.His145Arg (c.434A>G) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely benign (0.1039); Very rare (popmax 0.000113%, nfe).

How common is CDKL5 p.His145Arg (c.434A>G) in the general population?

CDKL5 p.His145Arg (c.434A>G) is very rare (popmax 0.000113%, nfe) (gnomAD).

What do computational predictors say about CDKL5 p.His145Arg (c.434A>G)?

AlphaMissense predicts likely benign (score 0.1039) — an in-silico prediction, not a clinical call.

CDKL5 p.His145Arg

c.434A>G · VCV4882292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1039 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000113%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1039	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -5.48	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 9.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	18.02	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000113% European (non-Finnish) · 1/884,443 alleles

Overall 9.21e-05% 1/1,085,358 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.His145Arg
Coding: c.434A>G
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18581921 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 145: the protein kinase domain; a UniProt-annotated variant site (in dee2; uncertain significance)

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

Similar variants

RS1 p.Asp145Asn Uncertain significance ★★★ ⚠ same residue
CDKL5 p.His145Tyr Uncertain significance ★ ⚠ same residue
RS1 p.Asp145= Likely benign ★ same residue
CDKL5 p.His145fs Likely pathogenic ★ same residue
CDKL5 c.146-1G>A Pathogenic ★★★ same type
CDKL5 p.Ala157Pro Likely pathogenic ★★★ same type
CDKL5 p.Ala157Val Likely pathogenic ★★★ same type
CDKL5 p.Ala40Val Pathogenic ★★★ same type

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-his145arg (accessed [today's date]).

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