Is CDK4 p.Ala269Val (c.806C>T) pathogenic?

CDK4 p.Ala269Val (c.806C>T) is classified Conflicting classifications of pathogenicity in CDK4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.1191); Very rare (popmax 0.00446%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Ala269Val (c.806C>T)?

CDK4 p.Ala269Val (c.806C>T) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDK4 p.Ala269Val (c.806C>T) in the general population?

CDK4 p.Ala269Val (c.806C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CDK4 p.Ala269Val (c.806C>T)?

AlphaMissense predicts likely benign (score 0.1191) — an in-silico prediction, not a clinical call.

CDK4 p.Ala269Val

c.806C>T · rs779161525 · VCV656768

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1191	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -5.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,892 alleles

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

Overall 0.000205% 3/1,461,680 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,446
European (non-Finnish)	8.48e-05%	1,179,878

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.Ala269Val
Coding: c.806C>T
MANE Select: NM_000075
dbSNP: rs779161525
Type: single nucleotide variant
Location: chr12:57749195 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 269: the protein kinase domain; an α-helix

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.Ala269Ser Uncertain significance ★ ⚠ same residue
CDK4 p.Ala269= 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
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-ala269val (accessed [today's date]).

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