Is CDKL5 p.Arg858Cys (c.2572C>T) pathogenic?

CDKL5 p.Arg858Cys (c.2572C>T) is classified Benign in CDKL5 (ClinVar, Expert panel, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.16); Very rare (popmax 0.00655%, amr); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Arg858Cys (c.2572C>T)?

CDKL5 p.Arg858Cys (c.2572C>T) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Arg858Cys (c.2572C>T) in the general population?

CDKL5 p.Arg858Cys (c.2572C>T) is very rare (popmax 0.00655%, amr) (gnomAD).

What do computational predictors say about CDKL5 p.Arg858Cys (c.2572C>T)?

AlphaMissense predicts likely benign (score 0.16) — an in-silico prediction, not a clinical call.

CDKL5 p.Arg858Cys

c.2572C>T · rs773760466 · VCV426292

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.16 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00655%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

BS2 BS1 BP5_Strong

Curation rationale (ClinGen, verbatim)

The highest population minor allele frequency of the p.Arg858Cys variant in CDKL5 in gnomAD v4.1 is 0.00004538 in the Ashkenazi Jewish population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0000083) for BS1, and therefore meets this criterion (BS1). The p.Arg858Cys variant is observed in at least 2 unaffected individuals (GeneDx- internal database) (BS2). The p.Arg858Cys variant is found in at least 3 patients with an alternate molecular basis of disease (Labcorp Genetics (formerly Invitae)- internal database; GeneDx- internal database) (BP5_Strong). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Arg858Cys variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP5_Strong). (CDKL5 Specifications v.5.0; curation approved on 01/28/2026)

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

Computational evidence

Protein change
AlphaMissense	0.16	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -8.74	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 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	25.7	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 0.00655% Admixed American · 3/45,818 alleles

Filtering AF 0.00192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00256% 31/1,210,110 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00655%	15,273
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,034
East Asian	0.00296%	33,750
European (non-Finnish)	0.00279%	35,799
African / African-American	0.00174%	57,333

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.Arg858Cys
Coding: c.2572C>T
MANE Select: NM_001323289
dbSNP: rs773760466
Type: single nucleotide variant
Location: chrX:18628446 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 858: the 'disordered' region; a UniProt-annotated variant site (in dee2); a UniProt-annotated variant site (found in a patient with infatile spasms; likely pathogenic); a UniProt-annotated variant site (in dee2; uncertain significance)

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.Arg858His Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKL5 p.Arg858fs Pathogenic ★ 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-arg858cys (accessed [today's date]).

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