Is CDK4 p.Val260fs (c.778del) pathogenic?

CDK4 p.Val260fs (c.778del) is classified Uncertain significance in CDK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). Associated with familial melanoma.

What condition is associated with CDK4 p.Val260fs (c.778del)?

CDK4 p.Val260fs (c.778del) is associated with familial melanoma (ClinVar).

How is Familial melanoma inherited?

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

CDK4 p.Val260fs

c.778del · VCV3653279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (7 of 8, 41 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.1	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: CDK4
Protein: p.Val260fs
Coding: c.778del
MANE Select: NM_000075
Type: Deletion
Location: chr12:57749223 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 260: the protein kinase domain; an α-helix

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.Val260= Conflicting classifications of pathogenicity ★ same residue
CDK4 p.Ala58_Arg62del Uncertain significance ★★ same condition
CDK4 p.Glu184fs Uncertain significance ★★ same condition
CDK4 p.Phe159fs Uncertain significance ★★ same condition
CDK4 c.683+8del Likely benign ★★ same condition
CDK4 c.523-37_523-17del Uncertain significance ★ same condition
CDK4 c.632+1_632+33del Uncertain significance ★ same condition
CDK4 p.Ala10fs 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-val260fs (accessed [today's date]).

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