Is CDKN2A p.Ala40Pro (c.118G>C) pathogenic?

CDKN2A p.Ala40Pro (c.118G>C) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: ambiguous (0.5607); Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.Ala40Pro (c.118G>C)?

CDKN2A p.Ala40Pro (c.118G>C) is associated with familial melanoma (ClinVar).

How common is CDKN2A p.Ala40Pro (c.118G>C) in the general population?

CDKN2A p.Ala40Pro (c.118G>C) 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.

What do computational predictors say about CDKN2A p.Ala40Pro (c.118G>C)?

AlphaMissense predicts ambiguous (score 0.5607) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala40Pro

c.118G>C · rs1554656295 · VCV1063406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5607 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.5607	ambiguous
REVEL	0.488	indeterminate
SaProt	LLR -6.02	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1.2, phastCons 0.001
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Ala40Pro
Coding: c.118G>C
MANE Select: NM_000077
dbSNP: rs1554656295
Type: single nucleotide variant
Location: chr9:21974710 (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

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.Ala40= Benign/Likely benign ★★ 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.151-1G>A Pathogenic ★★ same condition
CDKN2A c.151-1G>C 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-ala40pro (accessed [today's date]).

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