Is CDK4 p.Ser218= (c.654T>C) pathogenic?

CDK4 p.Ser218= (c.654T>C) is classified Benign/Likely benign in CDK4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-26). Very rare (popmax 0.0022%, sas); Associated with familial melanoma.

What condition is associated with CDK4 p.Ser218= (c.654T>C)?

CDK4 p.Ser218= (c.654T>C) is associated with familial melanoma, melanoma, cutaneous malignant, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Ser218= (c.654T>C) in the general population?

CDK4 p.Ser218= (c.654T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Familial melanoma inherited?

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

CDK4 p.Ser218=

c.654T>C · rs766518915 · VCV1118809

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.054	moderately benign-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.1	GERP 1, phastCons 0.99
Overall
CADD	8.882	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000205% 3/1,461,870 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,545
European (non-Finnish)	8.47e-05%	1,180,034

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.Ser218=
Coding: c.654T>C
MANE Select: NM_005981 · reported on NM_000075
dbSNP: rs766518915
Type: single nucleotide variant
Location: chr12:57749483 (GRCh38)

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: melanoma, cutaneous malignant, susceptibility to, 3 hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

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-ser218 (accessed [today's date]).

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