Is CDK2AP1 p.Pro45Leu (c.134C>T) pathogenic?

CDK2AP1 p.Pro45Leu (c.134C>T) is classified Uncertain significance in CDK2AP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely pathogenic (0.8361); Very rare (popmax 0.0011%, sas).

How common is CDK2AP1 p.Pro45Leu (c.134C>T) in the general population?

CDK2AP1 p.Pro45Leu (c.134C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CDK2AP1 p.Pro45Leu (c.134C>T)?

AlphaMissense predicts likely pathogenic (score 0.8361) — an in-silico prediction, not a clinical call.

CDK2AP1 p.Pro45Leu

c.134C>T · rs1271472566 · VCV2613656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8361	likely pathogenic
REVEL	0.542	indeterminate
SaProt	LLR -1.49	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 5,492 bp · p 9.7e-08 · regional, not allelic
Overall
CADD	32.0	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 0.0011% South Asian · 1/90,974 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000373% 6/1,609,562 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,920
South Asiangrpmax	0.0011%	90,974
European (non-Finnish)	0.00034%	294,029

Finnish 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: CDK2AP1
Protein: p.Pro45Leu
Coding: c.134C>T
MANE Select: NM_004642
dbSNP: rs1271472566
Type: single nucleotide variant
Location: chr12:123267204 (GRCh38)
Gene constraint: LOEUF 1.522 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 1 PDB

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.Arg111Trp 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

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-pro45leu (accessed [today's date]).

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