Is CDK4 p.Arg209Cys (c.625C>T) pathogenic?

CDK4 p.Arg209Cys (c.625C>T) is classified Conflicting classifications of pathogenicity in CDK4 (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1233); Ultra-rare (popmax 0.0417%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDK4 p.Arg209Cys (c.625C>T)?

CDK4 p.Arg209Cys (c.625C>T) is associated with hereditary neoplastic syndrome, melanoma, cutaneous malignant, susceptibility to, 3, familial melanoma (ClinVar).

How common is CDK4 p.Arg209Cys (c.625C>T) in the general population?

CDK4 p.Arg209Cys (c.625C>T) is ultra-rare (popmax 0.0417%, nfe) (gnomAD).

What do computational predictors say about CDK4 p.Arg209Cys (c.625C>T)?

AlphaMissense predicts likely benign (score 0.1233) — an in-silico prediction, not a clinical call.

CDK4 p.Arg209Cys

c.625C>T · rs140644696 · VCV135825

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.1233 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1233	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -8.09	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,189 bp · p 2e-07 · regional, not allelic
Overall
CADD	36.0	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 0.0417% European (non-Finnish) · 491/1,177,386 alleles

Filtering AF 0.0386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0374%

Overall 0.0333% 536/1,611,212 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0417%	2,398
Remaining individualsnot grpmax-eligible	0.0336%	2,972
Finnishnot grpmax-eligible	0.0125%	8,002
South Asian	0.00989%	10,110
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,799
African / African-American	0.00667%	14,988

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.Arg209Cys
Coding: c.625C>T
MANE Select: NM_000075
dbSNP: rs140644696
Type: single nucleotide variant
Location: chr12:57750663 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.57 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.56 · 15 PDB
Residue 209: the protein kinase domain; an α-helix

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: melanoma, cutaneous malignant, susceptibility to, 3 familial melanoma

Similar variants

CDK4 p.Arg209His Uncertain significance ★★ ⚠ same residue
CDK4 p.Arg209Leu Uncertain significance ★ same residue
CDK4 p.Arg209= 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-arg209cys (accessed [today's date]).

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