Is CDK4 p.Leu178= (c.534C>T) pathogenic?

CDK4 p.Leu178= (c.534C>T) is classified Benign/Likely benign in CDK4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-26). Very rare (popmax 0.00534%, afr); Associated with melanoma, cutaneous malignant, susceptibility to, 3.

What condition is associated with CDK4 p.Leu178= (c.534C>T)?

CDK4 p.Leu178= (c.534C>T) is associated with melanoma, cutaneous malignant, susceptibility to, 3, hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDK4 p.Leu178= (c.534C>T) in the general population?

CDK4 p.Leu178= (c.534C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

CDK4 p.Leu178=

c.534C>T · rs11547327 · VCV485484

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

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 3	GERP -0.2, phastCons 1
Overall
CADD	7.829	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,930 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,592 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,732
East Asian	0.00223%	44,900

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.Leu178=
Coding: c.534C>T
MANE Select: NM_000075
dbSNP: rs11547327
Type: single nucleotide variant
Location: chr12:57750754 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 178: the protein kinase domain; an α-helix

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

Also linked: hereditary neoplastic syndrome familial melanoma

Similar variants

CDK4 p.Leu178Phe Uncertain significance ★★ ⚠ 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
CDK4 c.355-4C>G Uncertain significance ★★ same condition
CDK4 c.632+5G>A Uncertain significance ★★ same condition
CDK4 c.820-3C>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-leu178 (accessed [today's date]).

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