Is CDKL4 p.Gly16Arg (c.46G>A) pathogenic?

CDKL4 p.Gly16Arg (c.46G>A) is classified Uncertain significance in CDKL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.5648); Rare (popmax 0.128%, amr).

How common is CDKL4 p.Gly16Arg (c.46G>A) in the general population?

CDKL4 p.Gly16Arg (c.46G>A) is rare (popmax 0.128%, amr) (gnomAD).

What do computational predictors say about CDKL4 p.Gly16Arg (c.46G>A)?

AlphaMissense predicts likely pathogenic (score 0.5648) — an in-silico prediction, not a clinical call.

CDKL4 p.Gly16Arg

c.46G>A · rs138111984 · VCV2588787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5648 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.128%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5648	likely pathogenic
REVEL	0.637	indeterminate
SaProt	LLR -14.40	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 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 54 kb · p 0.23 · regional, not allelic
Overall
CADD	31.0	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 0.128% Admixed American · 76/59,488 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0961%

Overall 0.00819% 132/1,611,638 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.128%	783
Remaining individualsnot grpmax-eligible	0.00481%	20,806
European (non-Finnish)	0.00432%	23,126
African / African-American	0.00267%	37,437

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: CDKL4
Protein: p.Gly16Arg
Coding: c.46G>A
MANE Select: NM_001397900
dbSNP: rs138111984
Type: single nucleotide variant
Location: chr2:39229487 (GRCh38)
Gene constraint: LOEUF 1.331 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.67
Residue 16: the protein kinase domain; a binding site

Full CDKL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKL4 p.Ala168Pro Uncertain significance ★ ⚠ same type
CDKL4 p.Ala186Thr Uncertain significance ★ ⚠ same type
CDKL4 p.Arg167Gln Uncertain significance ★ ⚠ same type
CDKL4 p.Arg299Cys Uncertain significance ★ ⚠ same type
CDKL4 p.Asn62Ser Uncertain significance ★ ⚠ same type
CDKL4 p.Asn65Thr Uncertain significance ★ ⚠ same type
CDKL4 p.Asn94Lys Uncertain significance ★ ⚠ same type
CDKL4 p.Asp159Asn 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/cdkl4-p-gly16arg (accessed [today's date]).

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