Is CDK4 p.Ala286Val (c.857C>T) pathogenic?

CDK4 p.Ala286Val (c.857C>T) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-25). AlphaMissense: likely pathogenic (0.7273); Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDK4 p.Ala286Val (c.857C>T)?

CDK4 p.Ala286Val (c.857C>T) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Ala286Val (c.857C>T) in the general population?

CDK4 p.Ala286Val (c.857C>T) 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.Ala286Val (c.857C>T)?

AlphaMissense predicts likely pathogenic (score 0.7273) — an in-silico prediction, not a clinical call.

CDK4 p.Ala286Val

c.857C>T · rs2140381155 · VCV1443282

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7273 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.7273	likely pathogenic
REVEL	0.508	indeterminate
SaProt	LLR -12.86	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	29.5	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

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.Ala286Val
Coding: c.857C>T
MANE Select: NM_005981 · reported on NM_000075
dbSNP: rs2140381155
Type: single nucleotide variant
Location: chr12:57748580 (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: 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-ala286val (accessed [today's date]).

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