Is CDKN2A p.Ala60= (c.180G>A) pathogenic?

CDKN2A p.Ala60= (c.180G>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-29). Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala60= (c.180G>A)?

CDKN2A p.Ala60= (c.180G>A) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Ala60= (c.180G>A) in the general population?

CDKN2A p.Ala60= (c.180G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

CDKN2A p.Ala60=

c.180G>A · rs1286147184 · VCV567892

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.179	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -4.1
Overall
CADD	5.422	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,802 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000313% 5/1,597,164 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,802
European (non-Finnish)	0.000339%	294,680

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.Ala60=
Coding: c.180G>A
MANE Select: NM_000077
dbSNP: rs1286147184
Type: single nucleotide variant
Location: chr9:21971179 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 60: an α-helix; a UniProt-annotated variant site (in); a UniProt-annotated variant site (in melanoma; loss of cdk4 binding); 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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial melanoma

Similar variants

CDKN2A p.Ala60Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala60Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Leu60Ile Uncertain significance ★★ same residue
CDKN2A p.Leu60Phe Uncertain significance ★★ same residue
CDKN2A p.Ala60Glu Likely pathogenic ★ same residue
CDKN2A p.Ala60Pro Uncertain significance ★ ⚠ same residue
CDKN2A p.Ala60Ser Uncertain significance ★ same residue
CDKN2A p.Leu60Arg 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-ala60 (accessed [today's date]).

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