Is CDKL5 p.Pro480Arg (c.1439C>G) pathogenic?

CDKL5 p.Pro480Arg (c.1439C>G) is classified Uncertain significance in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: ambiguous (0.383); Very rare (popmax 0.000112%, nfe).

How common is CDKL5 p.Pro480Arg (c.1439C>G) in the general population?

CDKL5 p.Pro480Arg (c.1439C>G) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about CDKL5 p.Pro480Arg (c.1439C>G)?

AlphaMissense predicts ambiguous (score 0.383) — an in-silico prediction, not a clinical call.

CDKL5 p.Pro480Arg

c.1439C>G · VCV4681076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.383 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.383	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -6.76	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	24.6	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 0.000112% European (non-Finnish) · 1/892,868 alleles

Overall 9.13e-05% 1/1,094,745 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.Pro480Arg
Coding: c.1439C>G
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18604363 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 480: the 'disordered' region

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-pro480arg (accessed [today's date]).

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