Is CDK18 p.Arg41Trp (c.121C>T) pathogenic?

CDK18 p.Arg41Trp (c.121C>T) is classified Uncertain significance in CDK18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.142); Ultra-rare (popmax 0.0329%, mid).

How common is CDK18 p.Arg41Trp (c.121C>T) in the general population?

CDK18 p.Arg41Trp (c.121C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CDK18 p.Arg41Trp (c.121C>T)?

AlphaMissense predicts likely benign (score 0.142) — an in-silico prediction, not a clinical call.

CDK18 p.Arg41Trp

c.121C>T · VCV4224528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.142 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.142	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -9.78	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 0.6	GERP -3.8
Regional constraint	o/e 0.97	unconstrained · MANE · 8,207 bp · p 0.52 · regional, not allelic
Overall
CADD	19.93	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00551% 89/1,614,012 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00602%	16,620
Admixed American	0.00333%	30,003

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: CDK18
Protein: p.Arg41Trp
Coding: c.121C>T
MANE Select: NM_212502
Type: single nucleotide variant
Location: chr1:205523288 (GRCh38)
Gene constraint: LOEUF 1.081 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.28

Full CDK18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK18 p.Arg41Gln Uncertain significance ★ ⚠ same residue
CDK18 c.273+26G>A Uncertain significance ★★ same type
CDK18 p.Arg162Cys Uncertain significance ★★ same type
CDK18 c.273+41G>A Uncertain significance ★ same type
CDK18 c.273+44C>T Uncertain significance ★ same type
CDK18 c.273+47A>C Uncertain significance ★ same type
CDK18 c.273+4A>T Uncertain significance ★ same type
CDK18 c.273+62G>C 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/cdk18-p-arg41trp (accessed [today's date]).

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