Is CDKL5 p.Thr35Ile (c.104C>T) pathogenic?

CDKL5 p.Thr35Ile (c.104C>T) is classified Likely pathogenic in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely pathogenic (0.9978); Absent from gnomAD v4.1; Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Thr35Ile (c.104C>T)?

CDKL5 p.Thr35Ile (c.104C>T) is associated with CDKL5 disorder (ClinVar).

How common is CDKL5 p.Thr35Ile (c.104C>T) in the general population?

CDKL5 p.Thr35Ile (c.104C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKL5 p.Thr35Ile (c.104C>T)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

CDKL5 p.Thr35Ile

c.104C>T · VCV3602046

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,158,891)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDKL5 disorder

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic ✓ concordant with ClinVar · top 9% in CDKL5
REVEL	0.365	indeterminate
SaProt	LLR -12.48	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 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	26.4	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

No allele count reported in gnomAD v4.1 (AN 1,158,891). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDKL5
Protein: p.Thr35Ile
Coding: c.104C>T
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18564481 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 35: the protein kinase domain; a turn

Full CDKL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CDKL5 disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDKL5 p.Thr35Ala Uncertain significance ★ ⚠ same residue
CDKL5 p.Thr35Pro Uncertain significance ★ ⚠ same residue
CDKL5 p.Thr35= Likely benign ★ same residue
CDKL5 c.146-1G>A Pathogenic ★★★ same condition
CDKL5 p.Ala157Pro Likely pathogenic ★★★ same condition
CDKL5 p.Ala157Val Likely pathogenic ★★★ same condition
CDKL5 p.Ala40Val Pathogenic ★★★ same condition
CDKL5 p.Arg178Gln Pathogenic ★★★ same condition

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/cdkl5-p-thr35ile (accessed [today's date]).

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