Is CDKL5 p.Ser438Arg (c.1314C>A) pathogenic?

CDKL5 p.Ser438Arg (c.1314C>A) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-15). AlphaMissense: likely pathogenic (0.8361); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Ser438Arg (c.1314C>A)?

CDKL5 p.Ser438Arg (c.1314C>A) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Ser438Arg (c.1314C>A) in the general population?

CDKL5 p.Ser438Arg (c.1314C>A) is absent from gnomAD v4.1 (gnomAD).

How is CDKL5-deficiency disorder inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKL5 p.Ser438Arg (c.1314C>A)?

AlphaMissense predicts likely pathogenic (score 0.8361) — an in-silico prediction, not a clinical call.

CDKL5 p.Ser438Arg

c.1314C>A · rs2518874147 · VCV2953907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8361 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 2

Computational evidence

Protein change
AlphaMissense	0.8361	likely pathogenic
REVEL	0.057	moderately benign-leaning
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	17.62	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.Ser438Arg
Coding: c.1314C>A
MANE Select: NM_001323289
dbSNP: rs2518874147
Type: single nucleotide variant
Location: chrX:18604238 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 438: the 'disordered' region

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

Disease context

developmental and epileptic encephalopathy, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CDKL5-deficiency disorder (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

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
CDKL5 p.Asp193Gly 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-ser438arg (accessed [today's date]).

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