Is CDK4 p.Pro8= (c.24A>C) pathogenic?

CDK4 p.Pro8= (c.24A>C) is classified Benign/Likely benign in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-04). Very rare (popmax 0.000254%, nfe); Associated with melanoma, cutaneous malignant, susceptibility to, 3.

What condition is associated with CDK4 p.Pro8= (c.24A>C)?

CDK4 p.Pro8= (c.24A>C) is associated with melanoma, cutaneous malignant, susceptibility to, 3 (ClinVar).

How common is CDK4 p.Pro8= (c.24A>C) in the general population?

CDK4 p.Pro8= (c.24A>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

CDK4 p.Pro8=

c.24A>C · rs756789126 · VCV1697371

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

melanoma, cutaneous malignant, susceptibility to, 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.4	GERP -2.4, phastCons 0.21
Overall
CADD	9.873	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,028 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,888 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.Pro8=
Coding: c.24A>C
MANE Select: NM_000075
dbSNP: rs756789126
Type: single nucleotide variant
Location: chr12:57751694 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 8: a β-strand; the protein kinase domain

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

Disease context

melanoma, cutaneous malignant, susceptibility to, 3 — 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.-100G>T Uncertain significance ★★ same condition
CDK4 c.-2G>A Uncertain significance ★★ same condition
CDK4 c.*319G>A Uncertain significance ★★ same condition
CDK4 p.Arg139Gln Uncertain significance ★★ ⚠ same condition
CDK4 p.Arg240Pro Uncertain significance ★★ ⚠ same condition
CDK4 p.Gln168His 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-pro8 (accessed [today's date]).

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