Is CDK4 p.Arg85Gln (c.254G>A) pathogenic?

CDK4 p.Arg85Gln (c.254G>A) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.0983); Ultra-rare (popmax 0.0165%, mid); Associated with familial melanoma.

What condition is associated with CDK4 p.Arg85Gln (c.254G>A)?

CDK4 p.Arg85Gln (c.254G>A) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Arg85Gln (c.254G>A) in the general population?

CDK4 p.Arg85Gln (c.254G>A) is ultra-rare (popmax 0.0165%, mid) (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.Arg85Gln (c.254G>A)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

CDK4 p.Arg85Gln

c.254G>A · rs587778184 · VCV133873

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -10.08	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Pangolin	Δ0.38	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.7	GERP -0.17, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	25.1	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000342% 5/1,461,852 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.0011%	91,070
European (non-Finnish)	0.000169%	590,019

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.Arg85Gln
Coding: c.254G>A
MANE Select: NM_000075
dbSNP: rs587778184
Type: single nucleotide variant
Location: chr12:57751307 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 85: the protein kinase domain; a β-strand

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.Arg85Gly Uncertain significance ★★ ⚠ same residue
CDK4 p.Arg85Trp Uncertain significance ★★ ⚠ same residue
CDK4 p.Arg85= Benign/Likely benign ★★ same residue
CDK4 p.Arg85Leu 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

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-arg85gln (accessed [today's date]).

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