# NM_000075.4(CDK4):c.60G>A (p.Val20=)

https://sugi.bio/variant/cdk4-p-val20

## Summary

**CDK4 p.Val20= (c.60G>A)** is classified **Benign/Likely benign** in CDK4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-14). Very rare (popmax 0.000169%, nfe); Associated with familial melanoma.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1595111186 · 3 submitters · 3 linked conditions · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the CDK4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to familial melanoma.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Multigenic/multifactorial |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CDK4 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Familial melanoma** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Melanoma — Very frequent (99-80%)
- Nevus — Very frequent (99-80%)
- Dry skin — Frequent (79-30%)
- Freckling — Frequent (79-30%)
- Abnormality of the hair — Frequent (79-30%)
- Abnormality of the lymphatic system — Frequent (79-30%)
- Retinopathy — Occasional (29-5%)
- Abnormality of extrapyramidal motor function — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003460/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDK4](https://sugi.bio/atlas/gene/CDK4/) |
| Protein change (HGVS p.) | p.Val20= |
| Coding change (HGVS c.) | c.60G>A |
| MANE Select transcript | [NM_000075](https://www.ncbi.nlm.nih.gov/nuccore/NM_000075) |
| dbSNP | [rs1595111186](https://www.ncbi.nlm.nih.gov/snp/rs1595111186/) |
| Variant type | single nucleotide variant |
| Location | chr12:57751658-57751658 (GRCh38) |
| ClinVar | [VCV734502](https://www.ncbi.nlm.nih.gov/clinvar/variation/734502/) |

**All HGVS expressions:** `LRG_490:g.5724G>A`, `NC_000012.11:g.58145441C>T`, `NC_000012.12:g.57751658C>T`, `NG_007484.2:g.5724G>A`, `NM_000075.4:c.60G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.588, GERP 0.954, phastCons 1 — weakly conserved position
- CADD: **PHRED 12.07**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.26 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,038 in the highest group · 3/1,614,056 alleles overall — very rare (popmax 0.000169%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| European (non-Finnish) (grpmax) | 0.000169% | 590,019 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CDK4** population constraint: LOEUF 0.61, pLI 0.56668, missense-Z 2.2555; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **melanoma, cutaneous malignant, susceptibility to, 3** — Definitive (AD)

## Protein context {#protein}

Residue **20** lies in the protein kinase domain; a β-strand; a binding site.

AlphaFold model confidence (whole protein): pLDDT 87.56, 68% of residues very-high.

**15 experimental structure(s)** (PDB): [2W96](https://www.rcsb.org/structure/2W96), [2W99](https://www.rcsb.org/structure/2W99), [2W9F](https://www.rcsb.org/structure/2W9F), [2W9Z](https://www.rcsb.org/structure/2W9Z), [3G33](https://www.rcsb.org/structure/3G33), [5FWK](https://www.rcsb.org/structure/5FWK).

## What this gene does {#gene-function}

*Describes the biological roles of CDK4 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CDK4's established molecular role includes cyclin-dependent protein serine/threonine kinase activity. p.Val20= falls in the protein kinase domain. In Reactome, CDK4 is annotated in disease pathway(s) including **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**, **Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4**.

**Disease mechanism (Reactome):** CDK4 loss or alteration is curated in [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069), [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9630791), [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9630794).

### Pathways affected {#pathways}

CDK4 participates in **19 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | other |
| ⚕ [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9630791) | other |
| ⚕ [Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9630794) | other |
| ⚕ [Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4](https://reactome.org/content/detail/R-HSA-9632697) | other |
| ⚕ [Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6](https://reactome.org/content/detail/R-HSA-9632700) | other |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | other |
| [Drug-mediated inhibition of CDK4/CDK6 activity](https://reactome.org/content/detail/R-HSA-9754119) | other |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | other |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | other |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | other |
| [PTK6 Regulates Cell Cycle](https://reactome.org/content/detail/R-HSA-8849470) | other |
| [RMTs methylate histone arginines](https://reactome.org/content/detail/R-HSA-3214858) | other |
| [SCF(Skp2)-mediated degradation of p27/p21](https://reactome.org/content/detail/R-HSA-187577) | other |
| [SPOP-mediated proteasomal degradation of PD-L1(CD274)](https://reactome.org/content/detail/R-HSA-9929491) | other |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | other |
| [Transcriptional regulation by RUNX2](https://reactome.org/content/detail/R-HSA-8878166) | other |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | other |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | other |
| [Ubiquitin-dependent degradation of Cyclin D](https://reactome.org/content/detail/R-HSA-75815) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cyclin-dependent protein serine/threonine kinase activity, cyclin binding.

**Biological process:** G1/S transition of mitotic cell cycle, positive regulation of cell population proliferation, response to xenobiotic stimulus, regulation of gene expression, positive regulation of G2/M transition of mitotic cell cycle, positive regulation of fibroblast proliferation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-14.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 3 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-14 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-24 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-09-24 |

## Associated conditions {#conditions}

[familial melanoma](https://sugi.bio/atlas/disease/familial-melanoma/), [melanoma, cutaneous malignant, susceptibility to, 3](https://sugi.bio/atlas/disease/melanoma-cutaneous-malignant-susceptibility-to-3/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Familial melanoma, Hereditary cancer-predisposing syndrome, Melanoma, cutaneous malignant, susceptibility to, 3, Hereditary melanoma, Hereditary cutaneous melanoma, Hereditary neoplastic syndrome, Tumor predisposition, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Cutaneous malignant melanoma 3.

## Similar variants {#similar}

Related CDK4 variant pages (same residue, condition, or type): [CDK4 p.Val20Ala](/variant/cdk4-p-val20ala), [CDK4 p.Arg24Cys](/variant/cdk4-p-arg24cys), [CDK4 p.Arg24His](/variant/cdk4-p-arg24his), [CDK4 c.354+3G>C](/variant/cdk4-c-354-plus-3g-c), [CDK4 c.354+5G>T](/variant/cdk4-c-354-plus-5g-t), [CDK4 c.355-4C>G](/variant/cdk4-c-355-minus-4c-g), [CDK4 c.632+5G>A](/variant/cdk4-c-632-plus-5g-a), [CDK4 c.820-3C>T](/variant/cdk4-c-820-minus-3c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 734502). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*