Is CDKL5 p.Arg31= (c.93A>G) pathogenic?

CDKL5 p.Arg31= (c.93A>G) is classified Likely benign in CDKL5 (ClinVar, Expert panel, 8 submitters; last evaluated 2022-09-01). Ultra-rare (popmax 0.0712%, mid); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Arg31= (c.93A>G)?

CDKL5 p.Arg31= (c.93A>G) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Arg31= (c.93A>G) in the general population?

CDKL5 p.Arg31= (c.93A>G) is ultra-rare (popmax 0.0712%, mid) (gnomAD).

CDKL5 p.Arg31=

c.93A>G · rs140332992 · VCV94115

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0712%, mid)

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for CDKL5 disorder. Applied ACMG criteria (verbatim):

BS2 BP7

Curation rationale (ClinGen, verbatim)

The p.Arg31= variant in CDKL5 is present in 3 female and 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg31= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Arg31= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Arg31= variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP7).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2, phastCons 1
Overall
CADD	8.877	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0712% Middle Eastern · 3/4,212 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00257% 30/1,168,821 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0712%	1,404
African / African-American	0.0159%	6,278
Admixed American	0.00219%	45,615
European (non-Finnish)	0.00198%	50,501

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.Arg31=
Coding: c.93A>G
MANE Select: NM_001323289
dbSNP: rs140332992
Type: single nucleotide variant
Location: chrX:18510848 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 31: the protein kinase domain; a β-strand

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.Arg31Gly 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-arg31 (accessed [today's date]).

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