Is CDKL3 p.Thr85Arg (c.254C>G) pathogenic?

CDKL3 p.Thr85Arg (c.254C>G) is classified Uncertain significance in CDKL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.9585); Ultra-rare (popmax 0.0166%, mid).

How common is CDKL3 p.Thr85Arg (c.254C>G) in the general population?

CDKL3 p.Thr85Arg (c.254C>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about CDKL3 p.Thr85Arg (c.254C>G)?

AlphaMissense predicts likely pathogenic (score 0.9585) — an in-silico prediction, not a clinical call.

CDKL3 p.Thr85Arg

c.254C>G · VCV4651601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9585 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9585	likely pathogenic
REVEL	0.443	indeterminate
SaProt	LLR -14.56	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 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 68 kb · p 0.16 · regional, not allelic
Overall
CADD	28.5	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 0.0166% Middle Eastern · 1/6,008 alleles

Filtering AF 0.000978% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000807%

Overall 0.00141% 22/1,562,362 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,008
Remaining individualsnot grpmax-eligible	0.00495%	20,186
European (non-Finnish)	0.00156%	63,932

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: CDKL3
Protein: p.Thr85Arg
Coding: c.254C>G
MANE Select: NM_001113575
Type: single nucleotide variant
Location: chr5:134360003 (GRCh38)
Gene constraint: LOEUF 1.523 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.87 · 1 PDB
Residue 85: the protein kinase domain; a β-strand

Full CDKL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKL3 p.Ala195Thr Uncertain significance ★ ⚠ same type
CDKL3 p.Ala235Ser Uncertain significance ★ ⚠ same type
CDKL3 p.Arg101Gln Uncertain significance ★ ⚠ same type
CDKL3 p.Arg111Pro Uncertain significance ★ ⚠ same type
CDKL3 p.Arg148Gln Uncertain significance ★ ⚠ same type
CDKL3 p.Arg164His Uncertain significance ★ ⚠ same type
CDKL3 p.Arg367Thr Uncertain significance ★ ⚠ same type
CDKL3 p.Arg463Ser 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/cdkl3-p-thr85arg (accessed [today's date]).

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