Is CDKN2A p.Ala5= (c.15G>A) pathogenic?

CDKN2A p.Ala5= (c.15G>A) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). Very rare (popmax 0.00224%, eas); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Ala5= (c.15G>A)?

CDKN2A p.Ala5= (c.15G>A) is associated with melanoma-pancreatic cancer syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Ala5= (c.15G>A) in the general population?

CDKN2A p.Ala5= (c.15G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

CDKN2A p.Ala5=

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.15G>A · rs768278082 · VCV2129711

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Conditions

melanoma-pancreatic cancer syndrome

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 0.075	GERP -3.8, phastCons 0.008
Overall
CADD	8.502	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,718 alleles

Overall 0.000138% 2/1,449,148 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,718
Remaining individualsnot grpmax-eligible	0.00161%	62,146

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.Ala5=
Coding: c.15G>A
MANE Select: NM_000077
dbSNP: rs768278082
Type: single nucleotide variant
Location: chr9:21974813 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 5: a β-strand; 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: familial melanoma

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Ala5Glu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala5Thr Uncertain significance ★★ same residue
CDKN2A p.Ala5Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Phe5Ile Uncertain significance ★★ same residue
CDKN2A p.Phe5Leu Uncertain significance ★★ same residue
CDKN2A p.Phe5Tyr Uncertain significance ★★ same residue
CDKN2A p.Phe5= Benign/Likely benign ★★ same residue
CDKN2A p.Phe5Ser Uncertain significance ★ same residue

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-ala5 (accessed [today's date]).

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