Is CDKL4 p.Leu200Pro (c.599T>C) pathogenic?

CDKL4 p.Leu200Pro (c.599T>C) is classified Uncertain significance in CDKL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: ambiguous (0.5376); Absent from gnomAD v4.1.

How common is CDKL4 p.Leu200Pro (c.599T>C) in the general population?

CDKL4 p.Leu200Pro (c.599T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL4 p.Leu200Pro (c.599T>C)?

AlphaMissense predicts ambiguous (score 0.5376) — an in-silico prediction, not a clinical call.

CDKL4 p.Leu200Pro

c.599T>C · VCV4651613

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5376 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5376	ambiguous
REVEL	0.726	pathogenic-leaning
SaProt	LLR -15.94	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	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

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.Leu200Pro
Coding: c.599T>C
MANE Select: NM_001397900
Type: single nucleotide variant
Location: chr2:39190358 (GRCh38)
Gene constraint: LOEUF 1.331 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.67
Residue 200: 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-leu200pro (accessed [today's date]).

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