Is CDKN2A p.Arg63= (c.187A>C) pathogenic?

CDKN2A p.Arg63= (c.187A>C) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-12). Very rare (popmax 0.000657%); Associated with familial melanoma.

What condition is associated with CDKN2A p.Arg63= (c.187A>C)?

CDKN2A p.Arg63= (c.187A>C) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Arg63= (c.187A>C) in the general population?

CDKN2A p.Arg63= (c.187A>C) is very rare (popmax 0.000657%) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Arg63=

c.187A>C · rs1190780216 · VCV485511

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000657%)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.23, phastCons 1
Overall
CADD	13.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000657%

Overall 0.000657% 1/152,168 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.Arg63=
Coding: c.187A>C
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1190780216
Type: single nucleotide variant
Location: chr9:21994145 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 63: an α-helix; the 'interaction with cdk5rap3 and mdm2' region; the 'disordered' region

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

Disease context

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDKN2A p.Arg63Ile Uncertain significance ★★ same residue
CDKN2A p.Arg63Lys Uncertain significance ★★ same residue
CDKN2A p.Leu63Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Leu63= Likely benign ★ same residue
CDKN2A p.Arg63del Uncertain significance ★ same residue
CDKN2A p.Arg63fs Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G 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-arg63 (accessed [today's date]).

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