Is CDK4 p.Val72Ala (c.215T>C) pathogenic?

CDK4 p.Val72Ala (c.215T>C) is classified Uncertain significance in CDK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-25). AlphaMissense: likely pathogenic (0.9543); Very rare (popmax 0.00223%, eas); Associated with familial melanoma.

What condition is associated with CDK4 p.Val72Ala (c.215T>C)?

CDK4 p.Val72Ala (c.215T>C) is associated with familial melanoma (ClinVar).

How common is CDK4 p.Val72Ala (c.215T>C) in the general population?

CDK4 p.Val72Ala (c.215T>C) is very rare (popmax 0.00223%, eas) (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.Val72Ala (c.215T>C)?

AlphaMissense predicts likely pathogenic (score 0.9543) — an in-silico prediction, not a clinical call.

CDK4 p.Val72Ala

c.215T>C · rs1180557312 · VCV2059420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9543 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.9543	likely pathogenic
REVEL	0.521	indeterminate
SaProt	LLR -11.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00223% East Asian · 1/44,870 alleles

Overall 6.2e-05% 1/1,613,790 alleles · very rare exomes 1/1,461,698 · genomes 0/152,092 · joint denominator

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.Val72Ala
Coding: c.215T>C
MANE Select: NM_000075
dbSNP: rs1180557312
Type: single nucleotide variant
Location: chr12:57751503 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 72: 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.Val72Asp Uncertain significance ★ ⚠ same residue
CDK4 p.Val72Gly 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

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-val72ala (accessed [today's date]).

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