# NM_000075.4(CDK4):c.251A>T (p.Asp84Val)

https://sugi.bio/variant/cdk4-p-asp84val

## Summary

**CDK4 p.Asp84Val (c.251A>T)** is classified **Uncertain significance** in CDK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-20). AlphaMissense: ambiguous (0.4356); Absent from gnomAD v4.1; Associated with familial melanoma.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2140387504 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CDK4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Asp84Val |
| Coding change (HGVS c.) | c.251A>T |
| MANE Select transcript | [NM_000075](https://www.ncbi.nlm.nih.gov/nuccore/NM_000075) |
| dbSNP | [rs2140387504](https://www.ncbi.nlm.nih.gov/snp/rs2140387504/) |
| Variant type | single nucleotide variant |
| Location | chr12:57751310-57751310 (GRCh38) |
| ClinVar | [VCV2830374](https://www.ncbi.nlm.nih.gov/clinvar/variation/2830374/) |

**All HGVS expressions:** `LRG_490:g.6072A>T`, `LRG_490t1:c.251A>T`, `NC_000012.11:g.58145093T>A`, `NC_000012.12:g.57751310T>A`, `NG_007484.2:g.6072A>T`, `NM_000075.4:c.251A>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4356) — no call either way
- REVEL 0.189 (benign-leaning)
- SaProt LLR -9.154 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 7.697, GERP 2.03, phastCons 1 — highly conserved
- CADD: **PHRED 24.6**. 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.*
- Regional missense constraint: **o/e 0.74** across the covering region of the MANE Select transcript (57,748,528–57,751,717), spanning 3,189 bp. Chi-square p 2e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **84** lies in the protein kinase domain; a β-strand.

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.Asp84Val 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-01-20 |

## Associated conditions {#conditions}

[familial melanoma](https://sugi.bio/atlas/disease/familial-melanoma/).

**Reported phenotype names (ClinVar):** Familial melanoma, Hereditary melanoma, Hereditary cutaneous melanoma.

## Similar variants {#similar}

Related CDK4 variant pages (same residue, condition, or type): [CDK4 p.Asp84=](/variant/cdk4-p-asp84), [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 2830374). 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.*