Is CDK4 p.Pro239Leu (c.716C>T) pathogenic?

CDK4 p.Pro239Leu (c.716C>T) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-06). AlphaMissense: likely pathogenic (0.8461); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Pro239Leu (c.716C>T)?

CDK4 p.Pro239Leu (c.716C>T) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDK4 p.Pro239Leu (c.716C>T) in the general population?

CDK4 p.Pro239Leu (c.716C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDK4 p.Pro239Leu (c.716C>T)?

AlphaMissense predicts likely pathogenic (score 0.8461) — an in-silico prediction, not a clinical call.

CDK4 p.Pro239Leu

c.716C>T · rs2140383035 · VCV2777318

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8461 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8461	likely pathogenic
REVEL	0.463	indeterminate
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	31.0	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.Pro239Leu
Coding: c.716C>T
MANE Select: NM_000075
dbSNP: rs2140383035
Type: single nucleotide variant
Location: chr12:57749285 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 239: the protein kinase domain

Full CDK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial melanoma

Similar variants

CDK4 p.Pro239Arg Uncertain significance ★ same residue
CDK4 p.Pro239His Uncertain significance ★ ⚠ same residue
CDK4 p.Pro239= 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
CDK4 c.354+5G>T Uncertain significance ★★ same condition
CDK4 c.355-4C>G 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-pro239leu (accessed [today's date]).

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