Is CDK2AP1 p.Arg111Trp (c.331C>T) pathogenic?

CDK2AP1 p.Arg111Trp (c.331C>T) is classified Uncertain significance in CDK2AP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely pathogenic (0.9921); Very rare (popmax 0.00134%, afr).

How common is CDK2AP1 p.Arg111Trp (c.331C>T) in the general population?

CDK2AP1 p.Arg111Trp (c.331C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CDK2AP1 p.Arg111Trp (c.331C>T)?

AlphaMissense predicts likely pathogenic (score 0.9921) — an in-silico prediction, not a clinical call.

CDK2AP1 p.Arg111Trp

c.331C>T · rs141641921 · VCV2282868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9921	likely pathogenic
REVEL	0.542	indeterminate
SaProt	LLR -15.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.99, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 5,492 bp · p 9.7e-08 · regional, not allelic
Overall
CADD	26.5	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 0.00134% African / African-American · 1/74,902 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,613,594 alleles · very rare exomes 12/1,461,450 · genomes 1/152,144 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,902
European (non-Finnish)	0.00102%	98,304

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: CDK2AP1
Protein: p.Arg111Trp
Coding: c.331C>T
MANE Select: NM_004642
dbSNP: rs141641921
Type: single nucleotide variant
Location: chr12:123261753 (GRCh38)
Gene constraint: LOEUF 1.522 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 1 PDB
Residue 111: a turn

Full CDK2AP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK2AP1 p.Gln57= Benign ★★ same type
CDK2AP1 p.Tyr63= Benign ★★ same type
CDK2AP1 p.Ala30Ser Uncertain significance ★ ⚠ same type
CDK2AP1 p.Gly43Arg Uncertain significance ★ ⚠ same type
CDK2AP1 p.Leu7Phe Uncertain significance ★ ⚠ same type
CDK2AP1 p.Met11Val Uncertain significance ★ ⚠ same type
CDK2AP1 p.Pro25His Uncertain significance ★ ⚠ same type
CDK2AP1 p.Pro45Leu 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/cdk2ap1-p-arg111trp (accessed [today's date]).

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