Is CDK4 p.Leu63= (c.187C>T) pathogenic?

CDK4 p.Leu63= (c.187C>T) is classified Likely benign in CDK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-22). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Leu63= (c.187C>T)?

CDK4 p.Leu63= (c.187C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Leu63= (c.187C>T) in the general population?

CDK4 p.Leu63= (c.187C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CDK4 p.Leu63=

c.187C>T · VCV3489504

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 2, phastCons 1
Overall
CADD	11.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.84e-05% 1/1,461,872 alleles · very rare

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: CDK4
Protein: p.Leu63=
Coding: c.187C>T
MANE Select: NM_000075
Type: single nucleotide variant
Location: chr12:57751531 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 63: the protein kinase domain; an α-helix

Full CDK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDK4 p.Arg24Cys Pathogenic ★★ same condition
CDK4 p.Arg24His Pathogenic ★★ same condition
CDK4 c.354+3G>C Uncertain significance ★★ same condition
CDK4 c.354+5G>T Uncertain significance ★★ same condition
CDK4 c.355-4C>G Uncertain significance ★★ same condition
CDK4 c.632+5G>A Uncertain significance ★★ same condition
CDK4 c.820-3C>T Uncertain significance ★★ same condition
CDK4 c.-2G>A Uncertain significance ★★ same condition

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/cdk4-p-leu63 (accessed [today's date]).

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