Is CDKL5 p.Ile3Phe (c.7A>T) pathogenic?

CDKL5 p.Ile3Phe (c.7A>T) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-06-21). AlphaMissense: likely benign (0.1217); Very rare (popmax 0.00297%, eas); Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Ile3Phe (c.7A>T)?

CDKL5 p.Ile3Phe (c.7A>T) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Ile3Phe (c.7A>T) in the general population?

CDKL5 p.Ile3Phe (c.7A>T) is very rare (popmax 0.00297%, eas) (gnomAD).

How is CDKL5-deficiency disorder inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKL5 p.Ile3Phe (c.7A>T)?

AlphaMissense predicts likely benign (score 0.1217) — an in-silico prediction, not a clinical call.

CDKL5 p.Ile3Phe

c.7A>T · rs138539908 · VCV408122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1217 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

developmental and epileptic encephalopathy, 2

Computational evidence

Protein change
AlphaMissense	0.1217	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00297% East Asian · 1/33,649 alleles

Filtering AF 0.000574% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000418%

Overall 0.000921% 11/1,194,152 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00297%	33,649
European (non-Finnish)	0.00113%	88,132

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: CDKL5
Protein: p.Ile3Phe
Coding: c.7A>T
MANE Select: NM_001323289
dbSNP: rs138539908
Type: single nucleotide variant
Location: chrX:18507103 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB

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

Disease context

developmental and epileptic encephalopathy, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CDKL5-deficiency disorder (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

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
CDKL5 p.Arg717= Likely pathogenic ★★★ same condition
CDKL5 p.Arg948Ter Pathogenic ★★★ same condition
CDKL5 p.Asp193Gly Likely 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-ile3phe (accessed [today's date]).

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