Is CDK4 p.Arg181Ter (c.541C>T) pathogenic?

CDK4 p.Arg181Ter (c.541C>T) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-07). Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDK4 p.Arg181Ter (c.541C>T)?

CDK4 p.Arg181Ter (c.541C>T) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Arg181Ter (c.541C>T) in the general population?

CDK4 p.Arg181Ter (c.541C>T) 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.

CDK4 p.Arg181Ter

c.541C>T · rs1595110257 · VCV1747429

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 5 of 8
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.38	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.9	GERP -0.37, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDK4
Protein: p.Arg181Ter
Coding: c.541C>T
MANE Select: NM_000075
dbSNP: rs1595110257
Type: single nucleotide variant
Location: chr12:57750747 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 181: the protein kinase domain

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

Also linked: hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDK4 p.Arg181Gln Uncertain significance ★★ ⚠ same residue
CDK4 p.Arg181Gly Uncertain significance ★★ ⚠ same residue
CDK4 p.Arg181Pro Uncertain significance ★ ⚠ same residue
CDK4 p.Arg181= Likely benign ★ same residue
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

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-arg181ter (accessed [today's date]).

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