Is CDKN2A p.Cys15Arg (c.43T>C) pathogenic?

CDKN2A p.Cys15Arg (c.43T>C) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-09). Very rare (popmax 6.89e-05%); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Cys15Arg (c.43T>C)?

CDKN2A p.Cys15Arg (c.43T>C) is associated with melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Cys15Arg (c.43T>C) in the general population?

CDKN2A p.Cys15Arg (c.43T>C) is very rare (popmax 6.89e-05%) (gnomAD).

CDKN2A p.Cys15Arg

Q: How is Familial atypical multiple mole melanoma syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.43T>C · rs1554659236 · VCV548785

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 6.89e-05%)

Conditions

melanoma-pancreatic cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.166	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.1
Overall
CADD	6.799	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.89e-05%

Overall 6.89e-05% 1/1,451,752 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDKN2A
Protein: p.Cys15Arg
Coding: c.43T>C
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1554659236
Type: single nucleotide variant
Location: chr9:21994289 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 15: an α-helix; the 'interaction with cdk5rap3 and mdm2' region

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

melanoma-pancreatic cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial melanoma

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Trp15Ter Pathogenic ★★ same residue
CDKN2A p.Trp15Cys Uncertain significance ★★ ⚠ same residue
CDKN2A p.Cys15Ter Uncertain significance ★ same residue
CDKN2A p.Trp15Leu Uncertain significance ★ ⚠ same residue
CDKN2A p.Cys15= Benign ★ same residue
CDKN2A p.Trp15Gly Likely benign ★ same residue
CDKN2A p.Trp15_Leu16insArg Conflicting classifications of pathogenicity ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdkn2a-p-cys15arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown