Is CDK4 p.Arg24Gly (c.70C>G) pathogenic?

CDK4 p.Arg24Gly (c.70C>G) is classified Uncertain significance in CDK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-20). AlphaMissense: likely pathogenic (0.9107); Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDK4 p.Arg24Gly (c.70C>G)?

CDK4 p.Arg24Gly (c.70C>G) is associated with familial melanoma (ClinVar).

How common is CDK4 p.Arg24Gly (c.70C>G) in the general population?

CDK4 p.Arg24Gly (c.70C>G) is absent from gnomAD v4.1 (gnomAD).

How is Familial melanoma inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDK4 p.Arg24Gly (c.70C>G)?

AlphaMissense predicts likely pathogenic (score 0.9107) — an in-silico prediction, not a clinical call.

CDK4 p.Arg24Gly

c.70C>G · rs11547328 · VCV1372933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9107 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,168)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.9107	likely pathogenic
REVEL	0.589	indeterminate
SaProt	LLR -14.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	33.0	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

No allele count reported in gnomAD v4.1 (AN 1,614,168). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDK4
Protein: p.Arg24Gly
Coding: c.70C>G
MANE Select: NM_000075
dbSNP: rs11547328
Type: single nucleotide variant
Location: chr12:57751648 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 24: a UniProt-annotated variant site (in cmm3; somatic and familial; generates a dominant oncogene resistant to inhibition by p16(ink4a)); a UniProt-annotated variant site (in cmm3); the protein kinase domain; a β-strand

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

Disease context

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDK4 p.Arg24Cys Pathogenic ★★ same residue
CDK4 p.Arg24His Pathogenic ★★ same residue
CDK4 p.Arg24Pro Uncertain significance ★ ⚠ same residue
CDK4 p.Arg24Ser Uncertain significance same residue
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

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-arg24gly (accessed [today's date]).

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