Is CDKL5 p.Met657Ile (c.1971G>A) pathogenic?

CDKL5 p.Met657Ile (c.1971G>A) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely benign (0.2009); Very rare (popmax 0.00176%, sas); Associated with Inborn genetic diseases.

What condition is associated with CDKL5 p.Met657Ile (c.1971G>A)?

CDKL5 p.Met657Ile (c.1971G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDKL5 p.Met657Ile (c.1971G>A) in the general population?

CDKL5 p.Met657Ile (c.1971G>A) is very rare (popmax 0.00176%, sas) (gnomAD).

What do computational predictors say about CDKL5 p.Met657Ile (c.1971G>A)?

AlphaMissense predicts likely benign (score 0.2009) — an in-silico prediction, not a clinical call.

CDKL5 p.Met657Ile

c.1971G>A · VCV4610332

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2009 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2009	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -5.67	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 8.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	21.5	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 0.00176% South Asian · 1/56,857 alleles

Overall 9.14e-05% 1/1,094,350 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.Met657Ile
Coding: c.1971G>A
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18608837 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 657: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDKL5 p.Met657Val Uncertain significance ★★ ⚠ same residue
CDKL5 c.2152+1G>A Pathogenic ★★ same condition
CDKL5 p.Gln605Ter Pathogenic ★★ same condition
CDKL5 p.Gln69Ter Pathogenic ★★ same condition
CDKL5 p.Gln865Ter Pathogenic ★★ same condition
CDKL5 p.Ala166Thr Uncertain significance ★★ ⚠ same condition
CDKL5 p.Arg81Gln Uncertain significance ★★ ⚠ same condition
CDKL5 p.Arg822Cys Uncertain significance ★★ ⚠ 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-met657ile (accessed [today's date]).

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