Is CDK4 p.Val242Ile (c.724G>A) pathogenic?

CDK4 p.Val242Ile (c.724G>A) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1493); Very rare (popmax 0.00445%, eas); Associated with familial melanoma.

What condition is associated with CDK4 p.Val242Ile (c.724G>A)?

CDK4 p.Val242Ile (c.724G>A) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Val242Ile (c.724G>A) in the general population?

CDK4 p.Val242Ile (c.724G>A) is very rare (popmax 0.00445%, 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.Val242Ile (c.724G>A)?

AlphaMissense predicts likely benign (score 0.1493) — an in-silico prediction, not a clinical call.

CDK4 p.Val242Ile

c.724G>A · rs876658903 · VCV231017

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1493 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.1493	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.7	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	22.5	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

Grpmax group 0.00445% East Asian · 2/44,900 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,450
South Asian	0.0011%	91,088
European (non-Finnish)	0.000169%	590,012

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.Val242Ile
Coding: c.724G>A
MANE Select: NM_005981 · reported on NM_000075
dbSNP: rs876658903
Type: single nucleotide variant
Location: chr12:57749277 (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-val242ile (accessed [today's date]).

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