Is CDKL4 p.Glu92Gly (c.275A>G) pathogenic?

CDKL4 p.Glu92Gly (c.275A>G) is classified Uncertain significance in CDKL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely benign (0.1854); Ultra-rare (popmax 0.0222%, nfe).

How common is CDKL4 p.Glu92Gly (c.275A>G) in the general population?

CDKL4 p.Glu92Gly (c.275A>G) is ultra-rare (popmax 0.0222%, nfe) (gnomAD).

What do computational predictors say about CDKL4 p.Glu92Gly (c.275A>G)?

AlphaMissense predicts likely benign (score 0.1854) — an in-silico prediction, not a clinical call.

CDKL4 p.Glu92Gly

c.275A>G · VCV3489603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1854 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1854	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -12.47	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 54 kb · p 0.23 · regional, not allelic
Overall
CADD	26.6	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 0.0222% European (non-Finnish) · 261/1,176,114 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.017% 272/1,603,770 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0222%	4,506
Remaining individualsnot grpmax-eligible	0.0113%	8,866
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,364
African / African-American	0.00269%	37,109
Admixed American	0.00172%	58,234

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.Glu92Gly
Coding: c.275A>G
MANE Select: NM_001397900
Type: single nucleotide variant
Location: chr2:39225854 (GRCh38)
Gene constraint: LOEUF 1.331 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.67
Residue 92: the protein kinase domain

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-glu92gly (accessed [today's date]).

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