Is CDKL5 p.Met949Ile (c.2847G>A) pathogenic?

CDKL5 p.Met949Ile (c.2847G>A) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-17). AlphaMissense: likely pathogenic (0.7536); Very rare (popmax 0.0002%); Associated with CDKL5-related disorder.

What condition is associated with CDKL5 p.Met949Ile (c.2847G>A)?

CDKL5 p.Met949Ile (c.2847G>A) is associated with CDKL5-related disorder (ClinVar).

How common is CDKL5 p.Met949Ile (c.2847G>A) in the general population?

CDKL5 p.Met949Ile (c.2847G>A) is very rare (popmax 0.0002%) (gnomAD).

What do computational predictors say about CDKL5 p.Met949Ile (c.2847G>A)?

AlphaMissense predicts likely pathogenic (score 0.7536) — an in-silico prediction, not a clinical call.

CDKL5 p.Met949Ile

c.2847G>A · rs1927149441 · VCV2636030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0002%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Conditions

CDKL5-related disorder

Computational evidence

Protein change
AlphaMissense	0.7536	likely pathogenic
SaProt	LLR -5.42	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.64, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	21.6	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 0.0002%

Overall 0.0002% 2/997,574 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.Met949Ile
Coding: c.2847G>A
MANE Select: NM_001323289
dbSNP: rs1927149441
Type: single nucleotide variant
Location: chrX:18628721 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 949: the 'disordered' region; a UniProt-annotated variant site (in dee2); a UniProt-annotated variant site (found in a patient with infatile spasms; likely pathogenic)

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

Disease context

CDKL5-related disorder

Similar variants

CDKL5 c.2152+5G>A Likely pathogenic ★★ same condition
CDKL5 p.Arg178Gly Pathogenic/Likely pathogenic ★★ same condition
CDKL5 p.Gln643Ter Pathogenic ★★ same condition
RS1 c.326+2T>G Pathogenic/Likely pathogenic ★★ same condition
RS1 c.522+1G>A Pathogenic ★★ same condition
RS1 p.Ala98Glu Pathogenic ★★ same condition
RS1 p.Arg197His Pathogenic/Likely pathogenic ★★ ⚠ same condition
RS1 p.Arg200Cys Pathogenic/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-met949ile (accessed [today's date]).

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