Is CDK4 p.Glu67Lys (c.199G>A) pathogenic?

CDK4 p.Glu67Lys (c.199G>A) is classified Uncertain significance in CDK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). AlphaMissense: likely benign (0.3167); Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDK4 p.Glu67Lys (c.199G>A)?

CDK4 p.Glu67Lys (c.199G>A) is associated with familial melanoma (ClinVar).

How common is CDK4 p.Glu67Lys (c.199G>A) in the general population?

CDK4 p.Glu67Lys (c.199G>A) 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.

What do computational predictors say about CDK4 p.Glu67Lys (c.199G>A)?

AlphaMissense predicts likely benign (score 0.3167) — an in-silico prediction, not a clinical call.

CDK4 p.Glu67Lys

c.199G>A · VCV3637630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3167 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.3167	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -3.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Glu67Lys
Coding: c.199G>A
MANE Select: NM_000075
Type: single nucleotide variant
Location: chr12:57751519 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 67: 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

For Familial melanoma (Orphanet):

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

Similar variants

CDK4 p.Glu67= Likely benign ★★ same residue
CDK4 p.Glu67Gln Uncertain significance ★ ⚠ same residue
CDK4 p.Glu67Gly Uncertain significance ★ ⚠ same residue
CDK4 p.Glu67Val Uncertain significance ★ ⚠ same residue
CDK4 p.Glu67Asp 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

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-glu67lys (accessed [today's date]).

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