Is CDK4 p.Phe278= (c.834T>C) pathogenic?

CDK4 p.Phe278= (c.834T>C) is classified Benign/Likely benign in CDK4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0533%, afr); Associated with familial melanoma.

What condition is associated with CDK4 p.Phe278= (c.834T>C)?

CDK4 p.Phe278= (c.834T>C) is associated with familial melanoma, melanoma, cutaneous malignant, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Phe278= (c.834T>C) in the general population?

CDK4 p.Phe278= (c.834T>C) is ultra-rare (popmax 0.0533%, afr) (gnomAD).

How is Familial melanoma inherited?

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

CDK4 p.Phe278=

c.834T>C · rs115576923 · VCV219965

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, afr)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.3	GERP 0.001, phastCons 1
Overall
CADD	10.87	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0533% African / African-American · 40/75,030 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.00304% 49/1,613,588 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0533%	1,876
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0096%	10,412
Admixed American	0.00167%	60,034
South Asian	0.0011%	91,070

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.Phe278=
Coding: c.834T>C
MANE Select: NM_005981 · reported on NM_000075
dbSNP: rs115576923
Type: single nucleotide variant
Location: chr12:57748603 (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-phe278 (accessed [today's date]).

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