Is CDK4 p.Arg139Gln (c.416G>A) pathogenic?

CDK4 p.Arg139Gln (c.416G>A) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-02). AlphaMissense: likely pathogenic (0.9903); Very rare (popmax 0.00432%, nfe); Associated with familial melanoma.

What condition is associated with CDK4 p.Arg139Gln (c.416G>A)?

CDK4 p.Arg139Gln (c.416G>A) is associated with familial melanoma, melanoma, cutaneous malignant, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Arg139Gln (c.416G>A) in the general population?

CDK4 p.Arg139Gln (c.416G>A) is very rare (popmax 0.00432%, nfe) (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.Arg139Gln (c.416G>A)?

AlphaMissense predicts likely pathogenic (score 0.9903) — an in-silico prediction, not a clinical call.

CDK4 p.Arg139Gln

c.416G>A · rs763652580 · VCV483289

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.9903	likely pathogenic
REVEL	0.575	indeterminate
SaProt	LLR -15.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.90 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 0.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00432% European (non-Finnish) · 51/1,180,034 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00328% 53/1,614,036 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,138
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,074

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.Arg139Gln
Coding: c.416G>A
MANE Select: NM_000075
dbSNP: rs763652580
Type: single nucleotide variant
Location: chr12:57751029 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 139: the protein kinase domain

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: melanoma, cutaneous malignant, susceptibility to, 3 hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDK4 p.Arg139Gly Uncertain significance ★★ ⚠ same residue
CDK4 p.Arg139Ter Uncertain significance ★★ same residue
CDK4 p.Arg139= 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-arg139gln (accessed [today's date]).

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