Is CDKL5 p.Met235Val (c.703A>G) pathogenic?

CDKL5 p.Met235Val (c.703A>G) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-19). AlphaMissense: likely pathogenic (0.6365); Very rare (popmax 0.000894%, nfe).

How common is CDKL5 p.Met235Val (c.703A>G) in the general population?

CDKL5 p.Met235Val (c.703A>G) is very rare (popmax 0.000894%, nfe) (gnomAD).

What do computational predictors say about CDKL5 p.Met235Val (c.703A>G)?

AlphaMissense predicts likely pathogenic (score 0.6365) — an in-silico prediction, not a clinical call.

CDKL5 p.Met235Val

c.703A>G · rs1925703356 · VCV1683801

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6365 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000894%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6365	likely pathogenic
REVEL	0.301	indeterminate
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.79	donor gain · deltas
Pangolin	Δ0.54	gain · loss 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.000894% European (non-Finnish) · 8/895,124 alleles

Filtering AF 0.000384% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000729% 8/1,097,780 alleles · very rare

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.Met235Val
Coding: c.703A>G
MANE Select: NM_001323289
dbSNP: rs1925703356
Type: single nucleotide variant
Location: chrX:18588102 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 235: the protein kinase domain; an α-helix

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

Similar variants

CDKL5 c.146-1G>A Pathogenic ★★★ same type
CDKL5 p.Ala157Pro Likely pathogenic ★★★ same type
CDKL5 p.Ala157Val Likely pathogenic ★★★ same type
CDKL5 p.Ala40Val Pathogenic ★★★ same type
CDKL5 p.Arg178Gln Pathogenic ★★★ same type
CDKL5 p.Arg717= Likely pathogenic ★★★ same type
CDKL5 p.Arg948Ter Pathogenic ★★★ same type
CDKL5 p.Asn71Asp Likely pathogenic ★★★ ⚠ 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/cdkl5-p-met235val (accessed [today's date]).

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