Is CDKL5 p.Pro895Ser (c.2683C>T) pathogenic?

CDKL5 p.Pro895Ser (c.2683C>T) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely benign (0.0584); Absent from gnomAD v4.1.

How common is CDKL5 p.Pro895Ser (c.2683C>T) in the general population?

CDKL5 p.Pro895Ser (c.2683C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Pro895Ser (c.2683C>T)?

AlphaMissense predicts likely benign (score 0.0584) — an in-silico prediction, not a clinical call.

CDKL5 p.Pro895Ser

c.2683C>T · rs2518899102 · VCV2578294

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0584 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0584	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 0.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	15.01	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Pro895Ser
Coding: c.2683C>T
MANE Select: NM_001323289
dbSNP: rs2518899102
Type: single nucleotide variant
Location: chrX:18628557 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 895: the 'disordered' region; a UniProt-annotated variant site (in dee2); a UniProt-annotated variant site (found in a patient with infatile spasms; likely pathogenic)

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

Similar variants

CDKL5 p.Pro895Leu Uncertain significance ★★★ ⚠ same residue
CDKL5 p.Pro895Thr Uncertain significance ★ ⚠ same residue
CDKL5 p.Pro895= Likely benign ★ same residue
CDKL5 p.Pro895fs Pathogenic ★ same residue
CDKL5 c.146-1G>A Pathogenic ★★★ same type
CDKL5 p.Ala157Pro Likely pathogenic ★★★ same type
CDKL5 p.Ala157Val Likely pathogenic ★★★ same type
CDKL5 p.Ala40Val Pathogenic ★★★ same type

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-pro895ser (accessed [today's date]).

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