Is CDKL2 p.Leu268Phe (c.804A>T) pathogenic?

CDKL2 p.Leu268Phe (c.804A>T) is classified Uncertain significance in CDKL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: ambiguous (0.5187); Very rare (popmax 0.00221%, sas).

How common is CDKL2 p.Leu268Phe (c.804A>T) in the general population?

CDKL2 p.Leu268Phe (c.804A>T) is very rare (popmax 0.00221%, sas) (gnomAD).

What do computational predictors say about CDKL2 p.Leu268Phe (c.804A>T)?

AlphaMissense predicts ambiguous (score 0.5187) — an in-silico prediction, not a clinical call.

CDKL2 p.Leu268Phe

c.804A>T · VCV3265521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Computational evidence

Protein change
AlphaMissense	0.5187	ambiguous
REVEL	0.541	indeterminate
SaProt	LLR -12.80	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.8	GERP -1.6, phastCons 0.022
Regional constraint	o/e 0.98	unconstrained · MANE · 44 kb · p 0.64 · regional, not allelic
Overall
CADD	20.8	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

Grpmax group 0.00221% South Asian · 2/90,392 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000206% 3/1,454,562 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,196
European (non-Finnish)	8.51e-05%	1,174,704

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDKL2
Protein: p.Leu268Phe
Coding: c.804A>T
MANE Select: NM_001330724
Type: single nucleotide variant
Location: chr4:75600361 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 3 PDB
Residue 268: the protein kinase domain

Full CDKL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKL2 p.Met215Leu Likely pathogenic ★ ⚠ same type
CDKL2 p.Ala148Gly Uncertain significance ★ ⚠ same type
CDKL2 p.Ala153Thr Uncertain significance ★ ⚠ same type
CDKL2 p.Ala279Asp Uncertain significance ★ ⚠ same type
CDKL2 p.Ala423Ser Uncertain significance ★ ⚠ same type
CDKL2 p.Arg149Gln Uncertain significance ★ ⚠ same type
CDKL2 p.Arg168Thr Uncertain significance ★ ⚠ same type
CDKL2 p.Arg252Cys Uncertain significance ★ ⚠ 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/cdkl2-p-leu268phe (accessed [today's date]).

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