Is CDKL2 p.Val10Phe (c.28G>T) pathogenic?

CDKL2 p.Val10Phe (c.28G>T) is classified Uncertain significance in CDKL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.9129); Ultra-rare (popmax 0.0404%, sas).

How common is CDKL2 p.Val10Phe (c.28G>T) in the general population?

CDKL2 p.Val10Phe (c.28G>T) is ultra-rare (popmax 0.0404%, sas) (gnomAD).

What do computational predictors say about CDKL2 p.Val10Phe (c.28G>T)?

AlphaMissense predicts likely pathogenic (score 0.9129) — an in-silico prediction, not a clinical call.

CDKL2 p.Val10Phe

c.28G>T · VCV4651592

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9129 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0404%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9129	likely pathogenic
REVEL	0.321	indeterminate
SaProt	LLR -12.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 44 kb · p 0.64 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0404% South Asian · 36/89,020 alleles

Filtering AF 0.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0264%

Overall 0.0035% 51/1,456,666 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0404%	2,473
Admixed American	0.00169%	58,998
Remaining individualsnot grpmax-eligible	0.0016%	62,366
European (non-Finnish)	0.0011%	90,682

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: CDKL2
Protein: p.Val10Phe
Coding: c.28G>T
MANE Select: NM_001330724
Type: single nucleotide variant
Location: chr4:75625961 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 3 PDB
Residue 10: the protein kinase domain; an α-helix; a binding site

Full CDKL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKL2 p.Val10Ala Uncertain significance ★ ⚠ same residue
CDKL2 p.Met215Leu Likely pathogenic ★ ⚠ same type
CDKL2 p.Ala148Gly Uncertain significance ★ ⚠ same type
CDKL2 p.Ala153Thr Uncertain significance ★ ⚠ same type
CDKL2 p.Ala279Asp Uncertain significance ★ ⚠ same type
CDKL2 p.Ala423Ser Uncertain significance ★ ⚠ same type
CDKL2 p.Arg149Gln Uncertain significance ★ ⚠ same type
CDKL2 p.Arg168Thr Uncertain significance ★ ⚠ 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/cdkl2-p-val10phe (accessed [today's date]).

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