Is CDKL2 p.His283Arg (c.848A>G) pathogenic?

CDKL2 p.His283Arg (c.848A>G) is classified Uncertain significance in CDKL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.0581); Ultra-rare (popmax 0.033%, mid).

How common is CDKL2 p.His283Arg (c.848A>G) in the general population?

CDKL2 p.His283Arg (c.848A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CDKL2 p.His283Arg (c.848A>G)?

AlphaMissense predicts likely benign (score 0.0581) — an in-silico prediction, not a clinical call.

CDKL2 p.His283Arg

c.848A>G · VCV3489585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0581 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0581	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -3.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.79, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 44 kb · p 0.64 · regional, not allelic
Overall
CADD	15.67	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

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00118% 19/1,613,710 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.008%	12,496
Admixed American	0.00167%	59,978
African / African-American	0.00133%	75,022
European (non-Finnish)	0.000848%	117,972

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.His283Arg
Coding: c.848A>G
MANE Select: NM_001330724
Type: single nucleotide variant
Location: chr4:75600317 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 3 PDB
Residue 283: the protein kinase domain; an α-helix

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

Similar variants

CDKL2 p.His283Gln Uncertain significance ★ ⚠ same residue
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

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-his283arg (accessed [today's date]).

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