Is CDKL4 p.Ile123Ser (c.368T>G) pathogenic?

CDKL4 p.Ile123Ser (c.368T>G) is classified Uncertain significance in CDKL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.5713); Absent from gnomAD v4.1.

How common is CDKL4 p.Ile123Ser (c.368T>G) in the general population?

CDKL4 p.Ile123Ser (c.368T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL4 p.Ile123Ser (c.368T>G)?

AlphaMissense predicts likely pathogenic (score 0.5713) — an in-silico prediction, not a clinical call.

CDKL4 p.Ile123Ser

c.368T>G · rs1677055215 · VCV3141638

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5713 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5713	likely pathogenic
REVEL	0.72	pathogenic-leaning
SaProt	LLR -14.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.47	acceptor loss · deltas
Pangolin	Δ0.47	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 54 kb · p 0.23 · regional, not allelic
Overall
CADD	23.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKL4
Protein: p.Ile123Ser
Coding: c.368T>G
MANE Select: NM_001397900
dbSNP: rs1677055215
Type: single nucleotide variant
Location: chr2:39204613 (GRCh38)
Gene constraint: LOEUF 1.331 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.67
Residue 123: 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-ile123ser (accessed [today's date]).

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