Is CDKL3 p.Ile121Phe (c.361A>T) pathogenic?

CDKL3 p.Ile121Phe (c.361A>T) is classified Uncertain significance in CDKL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.8676); Absent from gnomAD v4.1.

How common is CDKL3 p.Ile121Phe (c.361A>T) in the general population?

CDKL3 p.Ile121Phe (c.361A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL3 p.Ile121Phe (c.361A>T)?

AlphaMissense predicts likely pathogenic (score 0.8676) — an in-silico prediction, not a clinical call.

CDKL3 p.Ile121Phe

c.361A>T · VCV4224714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8676 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8676	likely pathogenic
REVEL	0.624	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.30	acceptor loss · deltas
Pangolin	Δ0.26	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 68 kb · p 0.16 · regional, not allelic
Overall
CADD	23.6	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

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: CDKL3
Protein: p.Ile121Phe
Coding: c.361A>T
MANE Select: NM_001113575
Type: single nucleotide variant
Location: chr5:134350427 (GRCh38)
Gene constraint: LOEUF 1.523 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.87 · 1 PDB
Residue 121: the protein kinase domain

Full CDKL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKL3 p.Ala195Thr Uncertain significance ★ ⚠ same type
CDKL3 p.Ala235Ser Uncertain significance ★ ⚠ same type
CDKL3 p.Arg101Gln Uncertain significance ★ ⚠ same type
CDKL3 p.Arg111Pro Uncertain significance ★ ⚠ same type
CDKL3 p.Arg148Gln Uncertain significance ★ ⚠ same type
CDKL3 p.Arg164His Uncertain significance ★ ⚠ same type
CDKL3 p.Arg367Thr Uncertain significance ★ ⚠ same type
CDKL3 p.Arg463Ser 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/cdkl3-p-ile121phe (accessed [today's date]).

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