Is CDKN2A p.Ala40= (c.120A>T) pathogenic?

CDKN2A p.Ala40= (c.120A>T) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-13). Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.Ala40= (c.120A>T)?

CDKN2A p.Ala40= (c.120A>T) is associated with familial melanoma, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Ala40= (c.120A>T) in the general population?

CDKN2A p.Ala40= (c.120A>T) is absent from gnomAD v4.1 (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Ala40=

c.120A>T · rs1435003150 · VCV1091471

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -8.1	GERP -4.1
Overall
CADD	9.496	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN2A
Protein: p.Ala40=
Coding: c.120A>T
MANE Select: NM_000077
dbSNP: rs1435003150
Type: single nucleotide variant
Location: chr9:21974708 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 40: 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

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

Also linked: melanoma-pancreatic cancer syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Ala40Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala40Pro Uncertain significance ★ ⚠ same residue
CDKN2A p.Ala40Thr Uncertain significance ★ ⚠ same residue
CDKN2A p.Ala40Val Uncertain significance ★ ⚠ same residue
CDKN2A p.Pro40= Likely benign ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A 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-ala40 (accessed [today's date]).

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