Is CDK2AP2 p.Val59Glu (c.176T>A) pathogenic?

CDK2AP2 p.Val59Glu (c.176T>A) is classified Uncertain significance in CDK2AP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely pathogenic (0.9316); Very rare (popmax 0.00133%, afr).

How common is CDK2AP2 p.Val59Glu (c.176T>A) in the general population?

CDK2AP2 p.Val59Glu (c.176T>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CDK2AP2 p.Val59Glu (c.176T>A)?

AlphaMissense predicts likely pathogenic (score 0.9316) — an in-silico prediction, not a clinical call.

CDK2AP2 p.Val59Glu

c.176T>A · rs1866560618 · VCV2340572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9316	likely pathogenic
REVEL	0.212	benign-leaning
SaProt	LLR -7.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 619 bp · p 0.86 · regional, not allelic
Overall
CADD	26.1	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 0.00133% African / African-American · 1/75,072 alleles

Overall 0.000205% 3/1,461,238 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,250
African / African-Americangrpmax	0.00133%	75,072

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CDK2AP2
Protein: p.Val59Glu
Coding: c.176T>A
MANE Select: NM_005851
dbSNP: rs1866560618
Type: single nucleotide variant
Location: chr11:67507596 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 1 PDB

Full CDK2AP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK2AP2 p.Gln60= Benign ★★ same type
CDK2AP2 p.Ala9Thr Uncertain significance ★ ⚠ same type
CDK2AP2 p.Glu83Gln Uncertain significance ★ ⚠ same type
CDK2AP2 p.Gly15Ser Uncertain significance ★ ⚠ same type
CDK2AP2 p.Met56Thr Uncertain significance ★ ⚠ same type
CDK2AP2 p.Met62Leu Uncertain significance ★ ⚠ same type
CDK2AP2 p.Pro19Leu Uncertain significance ★ ⚠ same type
CDK2AP2 p.Pro26Leu 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/cdk2ap2-p-val59glu (accessed [today's date]).

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