NM_000075.4:c.719G>C (p.Arg240Pro) is a missense variant in CDK4 exon 7, currently classified as Uncertain significance by five clinical laboratories in ClinVar (Variation ID: 495534).1 This variant is extremely rare in population databases, observed in 2 of 251,364 alleles (AF=0.0008%) in gnomAD v2.1 and 4 of 1,614,198 alleles (AF=0.00025%) in gnomAD v4.1, with no homozygotes, meeting PM2 at supporting strength.2 Multiple in silico tools predict a benign effect: REVEL score 0.097, BayesDel score -0.331, and SpliceAI max delta 0.02, meeting BP4 at supporting benign strength.3 No variant-specific functional data, de novo observations, case-control data, or segregation data were identified to support other pathogenic or benign criteria.4 The variant is in the CDK4 protein kinase domain at residue Arg240, but no statistically significant hotspot or domain-level PM1 specification was found in the current evidence. Overall, the evidence for pathogenicity (PM2_supporting) is balanced by evidence for a benign effect (BP4_supporting), yielding a classification of Uncertain significance under the generic ACMG/AMP 2015 framework.
CDK4
Final classification
VUS
CDK4 c.719G>C · p.Arg240Pro
CDK4
NM_000075.4:c.719G>C (p.Arg240Pro) is a missense variant in CDK4 exon 7, currently classified as Uncertain significance by five clinical laboratories in ClinVar (Variation ID: 495534).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CDK4 c.719G>C
PM2 + BP4
→
VUS
Gene diagram
· NM_000075.4 · variants mapped to exon structure
CDK4
NM_000075.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent or extremely rare in large population databases. In gnomAD v2.1, it is observed in 2/251,364 alleles (AF=0.0008%), and in gnomAD v4.1 in 4/1,614,198 alleles (AF=0.00025%), with no homozygotes in either dataset. Both frequencies are well below the 0.1% threshold for PM2.
gnomAD v2.1: 2/251364 allelesAF=7.96e-06
✓
BP4
supporting
Benign
Multiple lines of computational evidence support a benign effect: REVEL score is 0.097 (benign), BayesDel score is -0.331 (benign), and SpliceAI predicts no splicing impact (max delta = 0.02). No in silico predictor suggests pathogenicity.
REVEL: 0.097 (well below 0.5 thresholdbenign)BayesDel: -0.330834 (negative score
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at the same codon producing the same amino acid change (p.Arg240Pro) has been reported as pathogenic.
PS2
No de novo occurrence data is available for this variant.
PS3
No variant-specific functional data is available.
PS4
No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls is available.
PM1
Residue Arg240 is within the CDK4 protein kinase domain, but the residue is not identified as a statistically significant hotspot (cancerhotspots.org), and no VCEP/CSPEC domain specification or critical-domain literature citation is present in the case materials to support PM1 application.
PM6
No de novo observation is reported for this variant.
PP1
No segregation data with the disease phenotype is available for this variant.
PP2
No gene-level missense constraint metric (Z-score, missense depletion ratio) is available in the case materials to assess whether CDK4 has a low rate of benign missense variation.
PP3
Multiple in silico predictors support a benign effect: REVEL score is 0.097 (well below pathogenicity threshold of ~0.5), BayesDel score is -0.331 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.02).
PP4
No case-specific phenotype or family history data is available to assess whether the patient's presentation is highly specific for CDK4-related disease.
PP5
ClinVar reports this variant as Uncertain significance with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
The variant allele frequency in gnomAD (v2.1: 0.0008%, v4.1: 0.00025%) is far below the BA1 threshold of >1%.
BS1
The variant allele frequency in gnomAD (v2.1: 0.0008%, v4.1: 0.00025%) is below the BS1 threshold of >0.3%.
BS2
No data is available demonstrating observation of this variant in healthy adults at sufficient frequency to meet BS2.
BS3
No well-established functional studies demonstrate a benign effect of this variant.
BS4
No segregation data is available to evaluate lack of cosegregation with disease.
BP2
No data is available demonstrating this variant observed in trans with a known pathogenic variant.
BP5
No data is available demonstrating this variant in a case with an established alternative molecular basis for disease.
BP6
ClinVar reports this variant as Uncertain significance, not benign/likely benign.
N/A · 4
PVS1 · PM5 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.47801e-06; MAF= 0.00025%, 4/1614198 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95659e-06; MAF= 0.00080%, 2/251364 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,614,198
0 hom
0 hom
Middle Eastern 1 / 6,062 |
0.016% |
Remaining individuals 1 / 62,510 |
0.0016% |
South Asian 1 / 91,080 |
0.0011% |
European (non-Finnish) 1 / 1,180,022 |
8.5e-05% |
+ 6 not observed (Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008%
· 2 / 251,364
0 hom
0 hom
South Asian 1 / 30,616 |
0.0033% |
European (non-Finnish) 1 / 113,700 |
0.00088% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 495534)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.097. BayesDel score = -0.330834.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR