Familial melanoma: genes and variants
Familial melanoma is linked to 4 analyzed proteins (CDKN2A, CDK4, POT1 and TERT). 17 DNA variants are known to cause it; 651 more are uncertain, and 9 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Familial melanoma
CDKN2A: Tumor suppressor ARF
The ARF product of CDKN2A is a tumor-suppressor protein that binds MDM2 and helps preserve p53 activity. By promoting cell-cycle arrest and apoptosis, it provides an important barrier to uncontrolled cell growth from within the nucleolus.
15 disease-causing and 237 uncertain variants in CDKN2A are linked to Familial melanoma.
CDK4: Cyclin-dependent kinase 4
Together with D-type cyclins, it phosphorylates RB-family proteins and commits cells to progress from G1 toward DNA replication. Amplification or pathway activation is common in cancer, while rare activating germline variants predispose to familial melanoma.
2 disease-causing and 414 uncertain variants in CDK4 are linked to Familial melanoma.
POT1: Protection of telomeres protein 1
It binds the single-stranded ends of telomeres and helps control telomerase access while preventing chromosome ends from being mistaken for DNA breaks. Germline loss-of-function variants predispose to several cancers, including melanoma, glioma, and chronic lymphocytic leukemia, and can produce unusually long telomeres.
0 disease-causing and 0 uncertain variants in POT1 are linked to Familial melanoma.
TERT: Telomerase reverse transcriptase
It extends telomeric DNA using an internal RNA template and helps counter progressive chromosome-end shortening in stem and proliferative cells. Loss-of-function variants cause telomere-biology disorders, while promoter activation and increased activity support unlimited proliferation in many cancers.
0 disease-causing and 0 uncertain variants in TERT are linked to Familial melanoma.
Weakly linked (only a few uncertain records): XRCC3.
Known disease-causing variants in Familial melanoma
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| CDKN2A R99P | 99 | Disease-causing (★★) | |
| CDK4 R24C | 24 | Protein kinase | Disease-causing (★★) |
| CDKN2A G125R | 125 | Disease-causing (★★) | |
| CDK4 R24H | 24 | Protein kinase | Disease-causing (★★) |
| CDKN2A R82L | 82 | Disease-causing (★★) | |
| CDKN2A R98Q | 98 | Disease-causing (★★) | |
| CDKN2A R122L | 122 | Disease-causing (★★) | |
| CDKN2A M48I | 48 | Interaction with CDK5RAP3 and MDM2 | Disease-causing (★★) |
| CDKN2A G65R | 65 | Disease-causing (★★) | |
| CDKN2A D68N | 68 | Disease-causing (★★) | |
| CDKN2A A76L | 76 | Disease-causing (★★) | |
| CDKN2A R87P | 87 | Disease-causing (★★) | |
| CDKN2A G102V | 102 | Disease-causing (★★) | |
| CDKN2A P72L | 72 | Disease-causing (★★) | |
| CDKN2A P94L | 94 | Disease-causing (★★) | |
| CDKN2A P126R | 126 | Disease-causing (★★) | |
| CDKN2A G83L | 83 | Disease-causing (★) |
Uncertain variants in Familial melanoma that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| CDKN2A R98G | 98 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R98Q at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.88 | |
| CDKN2A R98L | 98 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R98Q at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.84 | |
| CDKN2A R122Q | 122 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R122L at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.98 | |
| CDKN2A R82P | 82 | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; R82L at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.59 | |
| CDKN2A R99H | 99 | Uncertain (★★) | +6: 3 other pathogenic changes within 3 positions; R99P at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.68 | |
| CDKN2A G83S | 83 | Uncertain (★★) | +6: 2 other pathogenic changes within 3 positions; G83L at the same position is pathogenic; seen in 2.7e-06 of gnomAD DNA copies; REVEL 0.652 | |
| CDKN2A R98P | 98 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; R98Q at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.84 | |
| CDKN2A D68E | 68 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; D68N at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.68 | |
| CDKN2A R82H | 82 | Uncertain (★★) | +6: 2 other pathogenic changes within 3 positions; R82L at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.59 |
Which prediction tools work for Familial melanoma
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaMissense: 84 out of 100
- SIFT: 82 out of 100
- MetaLR: 61 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Same protein, different disease
- Melanoma-pancreatic cancer syndrome is also caused by CDKN2A variants; they fall in the same places as the Familial melanoma variants (11 disease-causing).
- Melanoma, cutaneous malignant, susceptibility to, 8 is also caused by CDKN2A variants; they fall partly in the same places as the Familial melanoma variants (6 disease-causing).
Diseases related to Familial melanoma
- Melanoma, cutaneous malignant, susceptibility to, 8, also linked to CDK4, CDKN2A and TERT
- Alzheimer disease, also linked to CDK4 and CDKN2A
- Dyskeratosis congenita, also linked to POT1 and TERT
- Lung adenocarcinoma, also linked to CDKN2A and TERT
- Hepatocellular carcinoma, also linked to CDKN2A and TERT
- Parkinson disease, also linked to CDK4 and CDKN2A
- Acute myeloid leukemia, also linked to TERT
- Non-small cell lung carcinoma, also linked to CDKN2A
- Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, also linked to TERT
- Idiopathic pulmonary fibrosis, also linked to TERT
- Melanoma-pancreatic cancer syndrome, also linked to CDKN2A
- Tumor predisposition syndrome 3, also linked to POT1
Frequently asked questions
Which genes are linked to Familial melanoma?
In CATVariant, Familial melanoma is linked to 4 analyzed proteins: CDKN2A (Tumor suppressor ARF), CDK4 (Cyclin-dependent kinase 4), POT1 (Protection of telomeres protein 1) and TERT (Telomerase reverse transcriptase).
How many genetic variants are linked to Familial melanoma?
695 variants: 17 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 651 are of uncertain significance or have conflicting reports.
Which uncertain variants in Familial melanoma look disease-causing?
9 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CDKN2A R98G, CDKN2A R98L, CDKN2A R122Q, CDKN2A R82P and CDKN2A R99H. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Familial melanoma?
Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.84, based on 13 disease-causing and 27 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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