Is CDK4 p.Asp228Ter (c.681dup) pathogenic?

CDK4 p.Asp228Ter (c.681dup) is classified Uncertain significance in CDK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). Associated with familial melanoma.

What condition is associated with CDK4 p.Asp228Ter (c.681dup)?

CDK4 p.Asp228Ter (c.681dup) 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.Asp228Ter

c.681dup · VCV4711009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1

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

Variant & gene context

Gene: CDK4
Protein: p.Asp228Ter
Coding: c.681dup
MANE Select: NM_000075
Type: Duplication
Location: chr12:57749455 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 228: 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.Asp228Glu Uncertain significance ★★ ⚠ same residue
CDK4 p.Cys78fs Uncertain significance ★★ same condition
CDK4 p.Glu86fs Uncertain significance ★★ same condition
CDK4 p.Gly46_Gly48dup Uncertain significance ★★ same condition
CDK4 c.684-10dup Likely benign ★★ same condition
CDK4 c.632+5dup Conflicting classifications of pathogenicity ★ same condition
CDK4 p.Ala248fs Uncertain significance ★ same condition
CDK4 p.Asn279fs 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-asp228ter (accessed [today's date]).

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