VCV000016928.20 - ClinVar

NM_000075.4(CDK4):c.70C>T (p.Arg24Cys)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

5 out of 7 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000075.4(CDK4):c.70C>T (p.Arg24Cys)

Variation ID: 16928 Accession: VCV000016928.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q14.1 12: 57751648 (GRCh38) [ NCBI UCSC ] 12: 58145431 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Feb 15, 2026	Jan 20, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000075.4:c.70C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000066.1:p.Arg24Cys	missense
NC_000012.12:g.57751648G>A
NC_000012.11:g.58145431G>A
NG_007484.2:g.5734C>T
LRG_490:g.5734C>T
LRG_490t1:c.70C>T
	P11802:p.Arg24Cys

... more HGVS ... less HGVS

Protein change

R24C

Other names

Canonical SPDI

NC_000012.12:57751647:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA126982 UniProtKB: P11802#VAR_006200 OMIM: 123829.0001 dbSNP: rs11547328 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CDK4		No evidence available	No evidence available	GRCh38 GRCh37	656	1223

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Melanoma, cutaneous malignant, susceptibility to, 3	Pathogenic; risk factor (2)	no assertion criteria provided	May 26, 2016	RCV000018436.6
Familial melanoma	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 20, 2026	RCV000168188.11
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 27, 2023	RCV000584153.6
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2016	RCV000484583.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 15, 2017) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Familial melanoma	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695325.1 First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015	Comment: show Variant summary: The CDK4 c.70C>T (p.Arg24Cys) variant involves the alteration of a conserved nucleotide and is located in protein kinase domain of the protein (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121378 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002). This variant has been reported in six unrelated cutaneous malignant melanoma families including evidence of cosegregation with disease (Zuo_1996, Ghiorzo_2012, Puntervoll_2013). In vivo mice-model study shows the recapitulation of melanoma phenotype (Rane_2002). The codon p.Arg24 is a mutational hot-spot in which another mutation p.Arg24His is known to be pathogenic. Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Apr 26, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000568686.3 First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017	Comment: show This pathogenic variant is denoted CDK4 c.70C>T at the cDNA level, p.Arg24Cys (R24C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported to segregate with melanoma in several melanoma families (Zuo 1996, Puntervoll 2013). Functional studies have shown that this variant disrupts binding with CDKN2A, resulting in resistance to CDKN2A inhibition and increased CDK4 kinase activity (Wolfel 1995, Rane 2002). CDK4 Arg24Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Arg24Cys occurs at a position that is conserved across species and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this pathogenic variant may have on protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Apr 30, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Color Diagnostics, LLC DBA Color Health Accession: SCV000689576.3 First in ClinVar: Feb 19, 2018 Last updated: Jan 12, 2022	Comment: show This missense variant replaces arginine with cysteine at codon 24 of the CDK4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown that this variant impairs interaction with CDKN2A (p16-INK4a) preventing inhibition by p16-INK4a and allowing for unregulated CDK4 kinase activity, cell cycle progression and cellular transformation (PMID: 11756559, 7652577, 9228064). This variant has been reported in individuals affected with melanoma (PMID: 8528263, 22804906 23384855) and has been shown to segregate with disease (PMID: 23384855, 8528263). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Pathogenic (Dec 27, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV002664138.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 11756559‚ 23384855‚ 7652577‚ 8528263 Comment: show The p.R24C pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the CDK4 gene, results from a C to T substitution at nucleotide position 70. The arginine at codon 24 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature to segregate with melanoma in six different families (Zuo L et al. Nat. Genet., 1996 Jan;12:97-9; Puntervoll HE et al. J. Med. Genet., 2013 Apr;50:264-70). Additionally, this variant has been shown to disrupt p16INK4a binding and inhibition of CDK4, which results in an increase in CDK4 kinase activity (Wölfel T et al. Science, 1995 Sep;269:1281-4). Mouse in vivo studies demonstrated that mice with this variant showed significantly increased susceptibility to the development of CDK4 related tumors (Rane SG et al. Mol. Cell. Biol., 2002 Jan;22:644-56). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 20, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial melanoma	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000218852.10 First in ClinVar: Mar 29, 2015 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 11756559‚ 23384855‚ 7652577‚ 8528263 Comment: show This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the CDK4 protein (p.Arg24Cys). This variant is present in population databases (rs11547328, gnomAD 0.006%). This missense change has been observed in individual(s) with melanoma (PMID: 8528263, 23384855). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16928). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CDK4 function (PMID: 7652577, 11756559). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 26, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Melanoma, cutaneous malignant, susceptibility to, 3	Counsyl Accession: SCV000488638.3 First in ClinVar: Oct 11, 2015 Last updated: Jun 29, 2025	Publications: PubMed (5) PubMed: 22804906‚ 23384855‚ 7652577‚ 8528263‚ 9228064 Comment: show This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

risk factor (Jan 01, 1996) N Not contributing to aggregate classification	no assertion criteria provided	MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 3	OMIM Accession: SCV000038718.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 06, 2019	Publications: PubMed (2) PubMed: 7652577‚ 8528263 Observation: 1 Collection method: literature only Allele origin: unknown Affected status: not provided more Observation 1 Collection method: literature only Allele origin: unknown Affected status: not provided Comment on evidence: In a cutaneous malignant melanoma-3 (CMM3; 609048) cell line, Wolfel et al. (1995) identified an arg24-to-cys (R24C) mutation in the CDK4 gene. The mutated CDK4 … (more) In a cutaneous malignant melanoma-3 (CMM3; 609048) cell line, Wolfel et al. (1995) identified an arg24-to-cys (R24C) mutation in the CDK4 gene. The mutated CDK4 allele was present in autologous cultured melanoma cells and metastatic tissue, but not in the patient's lymphocytes, indicating a somatic mutation. The R24C mutation was part of the CDK4 peptide recognized by cytolytic T lymphocytes and prevented binding of the CDK4 inhibitor p16(INK4A) (600160), but not of p21 (300237) or of p27 (KIP1; 600778). The results suggested that mutation of CDK4 disrupted the cell cycle regulation exerted by the tumor suppressor p16, resulting in a genetic predisposition to melanoma. The same mutation, typical of a UV lesion, was found in 1 additional melanoma among 28 melanomas analyzed. The mutated CDK4 protein had been identified as a tumor-specific antigen recognized by HLA-A 2.1 restricted autologous cytolytic T lymphocytes in the human melanoma tissue. Wolfel et al. (1995) suggested that the tumor-specific antigen defined by the R24C mutation in this patient became a target of tumor rejection responses because the patient had remained free of detectable disease for 7 years. Zuo et al. (1996) identified the R24C mutation as a germline mutation in 2 families with malignant melanoma. The mutation was detected in 11 of 11 melanoma patients, 2 of 17 unaffected individuals, and in none of 5 spouses. Although the R24C mutation has a specific effect on the CDK4 p16(INK4A)-binding domain, it has no effect on the ability of CDK4 to bind cyclin D and form a functional kinase. Zuo et al. (1996) concluded that the germline R24C mutation generates a dominant oncogene that is resistant to normal physiologic inhibition by p16(INK4A). They noted that the only previous example of a dominant oncogene transmitted in the human germline was the RET (164761) gene that gives rise to MEN2A (171400), MEN2B (162300), and medullary thyroid carcinoma (171400). (less)

Comment:

Variant summary: The CDK4 c.70C>T (p.Arg24Cys) variant involves the alteration of a conserved nucleotide and is located in protein kinase domain of the protein (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121378 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002). This variant has been reported in six unrelated cutaneous malignant melanoma families including evidence of cosegregation with disease (Zuo_1996, Ghiorzo_2012, Puntervoll_2013). In vivo mice-model study shows the recapitulation of melanoma phenotype (Rane_2002). The codon p.Arg24 is a mutational hot-spot in which another mutation p.Arg24His is known to be pathogenic. Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

This pathogenic variant is denoted CDK4 c.70C>T at the cDNA level, p.Arg24Cys (R24C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported to segregate with melanoma in several melanoma families (Zuo 1996, Puntervoll 2013). Functional studies have shown that this variant disrupts binding with CDKN2A, resulting in resistance to CDKN2A inhibition and increased CDK4 kinase activity (Wolfel 1995, Rane 2002). CDK4 Arg24Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Arg24Cys occurs at a position that is conserved across species and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this pathogenic variant may have on protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.

Comment:

This missense variant replaces arginine with cysteine at codon 24 of the CDK4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown that this variant impairs interaction with CDKN2A (p16-INK4a) preventing inhibition by p16-INK4a and allowing for unregulated CDK4 kinase activity, cell cycle progression and cellular transformation (PMID: 11756559, 7652577, 9228064). This variant has been reported in individuals affected with melanoma (PMID: 8528263, 22804906 23384855) and has been shown to segregate with disease (PMID: 23384855, 8528263). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

The p.R24C pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the CDK4 gene, results from a C to T substitution at nucleotide position 70. The arginine at codon 24 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature to segregate with melanoma in six different families (Zuo L et al. Nat. Genet., 1996 Jan;12:97-9; Puntervoll HE et al. J. Med. Genet., 2013 Apr;50:264-70). Additionally, this variant has been shown to disrupt p16INK4a binding and inhibition of CDK4, which results in an increase in CDK4 kinase activity (Wölfel T et al. Science, 1995 Sep;269:1281-4). Mouse in vivo studies demonstrated that mice with this variant showed significantly increased susceptibility to the development of CDK4 related tumors (Rane SG et al. Mol. Cell. Biol., 2002 Jan;22:644-56). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the CDK4 protein (p.Arg24Cys). This variant is present in population databases (rs11547328, gnomAD 0.006%). This missense change has been observed in individual(s) with melanoma (PMID: 8528263, 23384855). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16928). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CDK4 function (PMID: 7652577, 11756559). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants.	Puntervoll HE	Journal of medical genetics	2013	PMID: 23384855
MC1R variation and melanoma risk in relation to host/clinical and environmental factors in CDKN2A positive and negative melanoma patients.	Ghiorzo P	Experimental dermatology	2012	PMID: 22804906
Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence.	Rane SG	Molecular and cellular biology	2002	PMID: 11756559
Identification of CDK4 sequences involved in cyclin D1 and p16 binding.	Coleman KG	The Journal of biological chemistry	1997	PMID: 9228064
Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma.	Zuo L	Nature genetics	1996	PMID: 8528263
A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma.	Wölfel T	Science (New York, N.Y.)	1995	PMID: 7652577

Text-mined citations for rs11547328 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026