Is CDKL5 p.Phe13Ser (c.38T>C) pathogenic?

CDKL5 p.Phe13Ser (c.38T>C) is classified Likely pathogenic in CDKL5 (ClinVar, Expert panel, 5 submitters; last evaluated 2025-06-25). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Phe13Ser (c.38T>C)?

CDKL5 p.Phe13Ser (c.38T>C) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Phe13Ser (c.38T>C) in the general population?

CDKL5 p.Phe13Ser (c.38T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Phe13Ser (c.38T>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

CDKL5 p.Phe13Ser

c.38T>C · rs1922605766 · VCV929426

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

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

PM2_Supporting PS2 PP4

Curation rationale (ClinGen, verbatim)

The p.Phe13Ser variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (internal database) and as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disorder (PMID 31313283) (PS2). The p.Phe13Ser variant in CDKL5 is present in an individual with a clinical phenotype suggestive of CDKL5 disorder (internal database - Labcorp Genetics (formerly Invitae)) (PP4). The p.Phe13Ser variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Phe13Ser variant in CDKL5 is classified as likely pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS2, PP4, PM2_Supporting). (CDKL5 Specifications v.4.1; curation approved on 06/25/2025)

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

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 4% in CDKL5
REVEL	0.623	indeterminate
SaProt	LLR -10.91	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	29.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKL5
Protein: p.Phe13Ser
Coding: c.38T>C
MANE Select: NM_001323289
dbSNP: rs1922605766
Type: single nucleotide variant
Location: chrX:18507134 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 13: 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.Phe13Ile Uncertain significance ★ ⚠ same residue
CDKL5 p.Phe13fs Likely 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-phe13ser (accessed [today's date]).

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