Is CDKL5 p.Leu703Val (c.2107C>G) pathogenic?

CDKL5 p.Leu703Val (c.2107C>G) is classified Likely benign in CDKL5 (ClinVar, Expert panel, 3 submitters; last evaluated 2023-08-28). AlphaMissense: likely benign (0.0798); Very rare (popmax 0.00434%, amr); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Leu703Val (c.2107C>G)?

CDKL5 p.Leu703Val (c.2107C>G) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Leu703Val (c.2107C>G) in the general population?

CDKL5 p.Leu703Val (c.2107C>G) is very rare (popmax 0.00434%, amr) (gnomAD).

What do computational predictors say about CDKL5 p.Leu703Val (c.2107C>G)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

CDKL5 p.Leu703Val

c.2107C>G · rs776965205 · VCV377648

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00434%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for CDKL5 disorder. Applied ACMG criteria (verbatim):

BS2 BP5

Curation rationale (ClinGen, verbatim)

The p.Leu703Val variant in CDKL5 is present in 1 female individual in gnomAD (0.0005%) (not sufficient to meet BS1 criteria). The p.Leu703Val variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Leu703Val variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Leu703Val variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.57, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	16.3	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

Grpmax group 0.00434% Admixed American · 2/46,066 alleles

Filtering AF 0.00072% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000269%

Overall 0.000273% 3/1,098,031 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00434%	23,033
European (non-Finnish)	0.000112%	895,568

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.Leu703Val
Coding: c.2107C>G
MANE Select: NM_001323289
dbSNP: rs776965205
Type: single nucleotide variant
Location: chrX:18609525 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 703: the 'disordered' region

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

Also linked: developmental and epileptic encephalopathy, 2

Similar variants

CDKL5 p.Leu703= 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
CDKL5 p.Arg717= Likely pathogenic ★★★ same condition
CDKL5 p.Arg948Ter 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-leu703val (accessed [today's date]).

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