Is CDKL2 p.Arg149Gln (c.446G>A) pathogenic?

CDKL2 p.Arg149Gln (c.446G>A) is classified Uncertain significance in CDKL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-14). AlphaMissense: likely pathogenic (0.9319); Ultra-rare (popmax 0.0167%, amr).

How common is CDKL2 p.Arg149Gln (c.446G>A) in the general population?

CDKL2 p.Arg149Gln (c.446G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about CDKL2 p.Arg149Gln (c.446G>A)?

AlphaMissense predicts likely pathogenic (score 0.9319) — an in-silico prediction, not a clinical call.

CDKL2 p.Arg149Gln

c.446G>A · rs755711267 · VCV2596577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9319 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9319	likely pathogenic
REVEL	0.455	indeterminate
SaProt	LLR -13.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 44 kb · p 0.64 · regional, not allelic
Overall
CADD	26.7	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 0.0167% Admixed American · 10/59,994 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.0018% 29/1,613,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
East Asian	0.00445%	22,449
Remaining individualsnot grpmax-eligible	0.0032%	31,239
South Asian	0.0022%	45,533
African / African-American	0.00133%	74,920
European (non-Finnish)	0.00102%	98,326

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.Arg149Gln
Coding: c.446G>A
MANE Select: NM_001330724
dbSNP: rs755711267
Type: single nucleotide variant
Location: chr4:75607279 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 3 PDB
Residue 149: the protein kinase domain; a UniProt-annotated variant site (in an ovarian mucinous carcinoma sample; somatic mutation); an α-helix

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.Arg168Thr Uncertain significance ★ ⚠ same type
CDKL2 p.Arg252Cys Uncertain significance ★ ⚠ same type
CDKL2 p.Arg252Gly 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-arg149gln (accessed [today's date]).

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