Is CDK4 p.Arg246His (c.737G>A) pathogenic?

CDK4 p.Arg246His (c.737G>A) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.2126); Very rare (popmax 0.00329%, sas); Associated with familial melanoma.

What condition is associated with CDK4 p.Arg246His (c.737G>A)?

CDK4 p.Arg246His (c.737G>A) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Arg246His (c.737G>A) in the general population?

CDK4 p.Arg246His (c.737G>A) is very rare (popmax 0.00329%, sas) (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.Arg246His (c.737G>A)?

AlphaMissense predicts likely benign (score 0.2126) — an in-silico prediction, not a clinical call.

CDK4 p.Arg246His

c.737G>A · rs372604524 · VCV485485

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.2126	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -9.54	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 4.7	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	22.1	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 0.00329% South Asian · 3/91,082 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00062% 10/1,614,008 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
African / African-American	0.00267%	37,462
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000254%	393,331

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.Arg246His
Coding: c.737G>A
MANE Select: NM_000075
dbSNP: rs372604524
Type: single nucleotide variant
Location: chr12:57749264 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 246: the protein kinase domain; an α-helix

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)

Similar variants

CDK4 p.Arg246Cys Uncertain significance ★★ ⚠ same residue
CDK4 p.Arg246fs Uncertain significance ★ same residue
CDK4 p.Arg246Leu Uncertain significance ★ ⚠ 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-arg246his (accessed [today's date]).

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