Is CDK4 p.Arg246Gly (c.736C>G) pathogenic?

CDK4 p.Arg246Gly (c.736C>G) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.4665); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Arg246Gly (c.736C>G)?

CDK4 p.Arg246Gly (c.736C>G) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDK4 p.Arg246Gly (c.736C>G) in the general population?

CDK4 p.Arg246Gly (c.736C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDK4 p.Arg246Gly (c.736C>G)?

AlphaMissense predicts ambiguous (score 0.4665) — an in-silico prediction, not a clinical call.

CDK4 p.Arg246Gly

c.736C>G · rs370258992 · VCV1051111

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4665	ambiguous
REVEL	0.151	moderately benign-leaning
SaProt	LLR -15.33	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.4	GERP -4.1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	20.9	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 0.00223% East Asian · 1/44,882 alleles

Overall 0.000137% 2/1,461,816 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
European (non-Finnish)	8.47e-05%	1,180,002

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.Arg246Gly
Coding: c.736C>G
MANE Select: NM_005981 · reported on NM_000075
dbSNP: rs370258992
Type: single nucleotide variant
Location: chr12:57749265 (GRCh38)

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

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-arg246gly (accessed [today's date]).

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