Is CDKL5 p.Leu271Pro (c.812T>C) pathogenic?

CDKL5 p.Leu271Pro (c.812T>C) is classified Pathogenic/Likely pathogenic in CDKL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-23). AlphaMissense: likely pathogenic (0.9926); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Leu271Pro (c.812T>C)?

CDKL5 p.Leu271Pro (c.812T>C) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Leu271Pro (c.812T>C) in the general population?

CDKL5 p.Leu271Pro (c.812T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Leu271Pro (c.812T>C)?

AlphaMissense predicts likely pathogenic (score 0.9926) — an in-silico prediction, not a clinical call.

CDKL5 p.Leu271Pro

c.812T>C · rs2518864219 · VCV2138479

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9926 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKL5 disorder

Computational evidence

Protein change
AlphaMissense	0.9926	likely pathogenic ✓ concordant with ClinVar
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -15.66	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	27.4	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.Leu271Pro
Coding: c.812T>C
MANE Select: NM_001323289
dbSNP: rs2518864219
Type: single nucleotide variant
Location: chrX:18595415 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 271: the protein kinase domain; an α-helix

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 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.Asn71Asp 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-leu271pro (accessed [today's date]).

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