Is CDKL5 p.Ala173Asp (c.518C>A) pathogenic?

CDKL5 p.Ala173Asp (c.518C>A) is classified Uncertain significance in CDKL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-13). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with Angelman syndrome-like.

What condition is associated with CDKL5 p.Ala173Asp (c.518C>A)?

CDKL5 p.Ala173Asp (c.518C>A) is associated with Angelman syndrome-like, developmental and epileptic encephalopathy, 2, CDKL5 disorder (ClinVar).

How common is CDKL5 p.Ala173Asp (c.518C>A) in the general population?

CDKL5 p.Ala173Asp (c.518C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Ala173Asp (c.518C>A)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

CDKL5 p.Ala173Asp

c.518C>A · VCV3344012

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Angelman syndrome-like

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic · top 4% in CDKL5
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -15.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, 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

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

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.Ala173Asp
Coding: c.518C>A
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18584317 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 173: the protein kinase domain; an α-helix

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

Disease context

Angelman syndrome-like — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 2 CDKL5 disorder

Similar variants

CDKL5 p.Ala173Val Uncertain significance ★ ⚠ same residue
RS1 p.Asn173= Likely benign ★ 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-ala173asp (accessed [today's date]).

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