Is CDKN2A p.Pro3= (c.9G>A) pathogenic?

CDKN2A p.Pro3= (c.9G>A) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-10). Very rare (popmax 0.00169%, amr); Associated with familial melanoma.

What condition is associated with CDKN2A p.Pro3= (c.9G>A)?

CDKN2A p.Pro3= (c.9G>A) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Pro3= (c.9G>A) in the general population?

CDKN2A p.Pro3= (c.9G>A) is very rare (popmax 0.00169%, amr) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Pro3=

c.9G>A · rs1057523441 · VCV389468

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

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 -0.35	GERP -3.5
Overall
CADD	7.673	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% Admixed American · 1/59,110 alleles

Filtering AF 0.00043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000314%

Overall 0.000751% 12/1,598,072 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,110
Remaining individualsnot grpmax-eligible	0.00161%	61,970
European (non-Finnish)	0.00085%	117,610

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.Pro3=
Coding: c.9G>A
MANE Select: NM_000077
dbSNP: rs1057523441
Type: single nucleotide variant
Location: chr9:21974819 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 3: the 'interaction with cdk5rap3 and mdm2' 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.Arg3Cys Uncertain significance ★★ same residue
CDKN2A p.Arg3His Uncertain significance ★★ same residue
CDKN2A p.Pro3Ala Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg3= Benign/Likely benign ★★ same residue
CDKN2A p.Arg3Leu Uncertain significance ★ same residue
CDKN2A p.Pro3Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Pro3Thr Uncertain significance ★ ⚠ 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-pro3 (accessed [today's date]).

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