Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001323289.2(CDKL5):c.656A>G (p.Gln219Arg)

CA412353461

2572403 (ClinVar)

Gene: CDKL5 (HGNC:6792)

Condition: CDKL5 disorder (MONDO:0100039)

Inheritance Mode: X-linked inheritance

UUID: 6db16dfc-f96f-46c9-b3c1-6205b63f926d

Approved on: 2026-08-25

Published on: 2026-09-24

HGVS expressions

NM_001323289.2(CDKL5):c.656A>G (p.Gln219Arg)

NM_001323289.2:c.656A>G

NC_000023.11:g.18588055A>G

CM000685.2:g.18588055A>G

NC_000023.10:g.18606175A>G

CM000685.1:g.18606175A>G

NC_000023.9:g.18516096A>G

NG_008475.1:g.167451A>G

ENST00000623535.2:c.656A>G

ENST00000635828.1:c.656A>G

ENST00000637881.1:c.656A>G

ENST00000674046.1:c.656A>G

ENST00000379989.6:c.656A>G

ENST00000379996.7:c.656A>G

ENST00000463994.4:c.656A>G

ENST00000623535.1:c.656A>G

ENST00000623610.1:n.370A>G

NM_001037343.1:c.656A>G

NM_003159.2:c.656A>G

NM_001323289.1:c.656A>G

NM_001037343.2:c.656A>G

NM_003159.3:c.656A>G

Likely Pathogenic

PM2_Supporting PS2 PS4_Supporting PM5 PP3

PP4

Evidence Links 0

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 6.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Gln219Arg variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (PMID: 39944418) (PS2). The p.Gln219Arg variant has been observed in at least 1 additional individual with CDKL5 disorder, in a de novo state (biological parentage unconfirmed) (PMID: 33219631) (PS4_Supporting). The variant is absent from gnomAD v4.1.1 (PM2_Supporting), and computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). A pathogenic missense variant (p.Gln219Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (ClinVar, ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel) (PM5). In summary, the p.Gln219Arg variant in CDKL5 is classified as Likely Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS2, PS4_Supporting, PP3, PM2_Supporting, PM5). CDKL5 Specifications v6.0; curation approved on 25-Aug-2026.

PM2_Supporting

The p.Gln219Arg variant in CDKL5 is absent from gnomAD v4.1.1 (PM2_Supporting).

PS2

The p.Gln219Arg variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (PMID:39944418) (PS2).

PS4_Supporting

The p.(Gln219Arg) variant has been observed in at least 2 individuals with CDKL5 disorder (PMID: 33219631, 399444418) (PS4_Supporting).

PM5

A pathogenic missense variant (p.Gln219Pro) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (ClinVar, ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel) (PM5).

PP3

Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).

PP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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