Is CDKN2A p.Ala20Pro (c.58G>C) pathogenic?

CDKN2A p.Ala20Pro (c.58G>C) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.9523); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala20Pro (c.58G>C)?

CDKN2A p.Ala20Pro (c.58G>C) is associated with hereditary neoplastic syndrome, melanoma-pancreatic cancer syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Ala20Pro (c.58G>C) in the general population?

CDKN2A p.Ala20Pro (c.58G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Ala20Pro (c.58G>C)?

AlphaMissense predicts likely pathogenic (score 0.9523) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala20Pro

c.58G>C · rs760065045 · VCV576362

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9523 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9523	likely pathogenic · top 5% in CDKN2A
REVEL	0.54	indeterminate
SaProt	LLR -14.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 1.1, phastCons 0.88
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.0	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.Ala20Pro
Coding: c.58G>C
MANE Select: NM_000077
dbSNP: rs760065045
Type: single nucleotide variant
Location: chr9:21974770 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 20: an α-helix; a UniProt-annotated variant site (in a lung tumor and melanoma); a UniProt-annotated variant site (in a biliary tract tumor); the 'interaction with cdk5rap3 and mdm2' 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: melanoma-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.Ala20Glu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala20Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala20Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala20Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala20Thr Uncertain significance ★ ⚠ same residue
CDKN2A p.Val20Ala Uncertain significance ★ same residue
CDKN2A p.Ala20= Likely benign ★ 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-ala20pro (accessed [today's date]).

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