Is CDKL2 p.Leu66Phe (c.196C>T) pathogenic?

CDKL2 p.Leu66Phe (c.196C>T) is classified Uncertain significance in CDKL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-05). AlphaMissense: likely pathogenic (0.9293); Ultra-rare (popmax 0.0704%, eas).

How common is CDKL2 p.Leu66Phe (c.196C>T) in the general population?

CDKL2 p.Leu66Phe (c.196C>T) is ultra-rare (popmax 0.0704%, eas) (gnomAD).

What do computational predictors say about CDKL2 p.Leu66Phe (c.196C>T)?

AlphaMissense predicts likely pathogenic (score 0.9293) — an in-silico prediction, not a clinical call.

CDKL2 p.Leu66Phe

c.196C>T · rs748664134 · VCV2533609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9293 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0704%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9293	likely pathogenic
REVEL	0.7	pathogenic-leaning
SaProt	LLR -14.87	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 1.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 44 kb · p 0.64 · regional, not allelic
Overall
CADD	23.3	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

Grpmax group 0.0704% East Asian · 31/44,038 alleles

Filtering AF 0.0509% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0443%

Overall 0.00205% 32/1,561,496 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0704%	1,421
Remaining individualsnot grpmax-eligible	0.00166%	60,160

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.Leu66Phe
Coding: c.196C>T
MANE Select: NM_001330724
dbSNP: rs748664134
Type: single nucleotide variant
Location: chr4:75614422 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 3 PDB
Residue 66: the protein kinase domain; a β-strand

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-leu66phe (accessed [today's date]).

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