Is CDKL5 p.Arg81Gln (c.242G>A) pathogenic?

CDKL5 p.Arg81Gln (c.242G>A) is classified Uncertain significance in CDKL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-10). AlphaMissense: likely pathogenic (0.9449); Very rare (popmax 0.00296%, eas); Associated with Inborn genetic diseases.

What condition is associated with CDKL5 p.Arg81Gln (c.242G>A)?

CDKL5 p.Arg81Gln (c.242G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDKL5 p.Arg81Gln (c.242G>A) in the general population?

CDKL5 p.Arg81Gln (c.242G>A) is very rare (popmax 0.00296%, eas) (gnomAD).

What do computational predictors say about CDKL5 p.Arg81Gln (c.242G>A)?

AlphaMissense predicts likely pathogenic (score 0.9449) — an in-silico prediction, not a clinical call.

CDKL5 p.Arg81Gln

c.242G>A · VCV3265534

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9449 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9449	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -11.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00296% East Asian · 1/33,809 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000456% 5/1,096,252 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00909%	11,004
East Asiangrpmax	0.00296%	33,809
European (non-Finnish)	0.000224%	446,935

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg81Gln
Coding: c.242G>A
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18575450 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 81: the protein kinase domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RS1 p.Ile81Asn Pathogenic ★ same residue
CDKL5 p.Arg81Gly Uncertain significance ★ ⚠ same residue
CDKL5 c.2152+1G>A Pathogenic ★★ same condition
CDKL5 p.Gln605Ter Pathogenic ★★ same condition
CDKL5 p.Gln69Ter Pathogenic ★★ same condition
CDKL5 p.Gln865Ter Pathogenic ★★ same condition
CDKL5 p.Ala166Thr Uncertain significance ★★ ⚠ same condition
CDKL5 p.Arg822Cys Uncertain significance ★★ ⚠ 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-arg81gln (accessed [today's date]).

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