Is CDK4 p.Arg85Trp (c.253C>T) pathogenic?

CDK4 p.Arg85Trp (c.253C>T) is classified Uncertain significance in CDK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-18). AlphaMissense: likely benign (0.3318); Very rare (popmax 0.0011%, sas); Associated with familial melanoma.

What condition is associated with CDK4 p.Arg85Trp (c.253C>T)?

CDK4 p.Arg85Trp (c.253C>T) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDK4 p.Arg85Trp (c.253C>T) in the general population?

CDK4 p.Arg85Trp (c.253C>T) is very rare (popmax 0.0011%, 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.Arg85Trp (c.253C>T)?

AlphaMissense predicts likely benign (score 0.3318) — an in-silico prediction, not a clinical call.

CDK4 p.Arg85Trp

c.253C>T · rs759017803 · VCV1520492

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3318 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.3318	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -12.76	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.93 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.4	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	29.6	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 0.0011% South Asian · 1/91,072 alleles

Overall 0.000186% 3/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,180,050

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg85Trp
Coding: c.253C>T
MANE Select: NM_000075
dbSNP: rs759017803
Type: single nucleotide variant
Location: chr12:57751308 (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.Arg85Gln Uncertain significance ★★ ⚠ same residue
CDK4 p.Arg85Gly 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-arg85trp (accessed [today's date]).

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