Is CDKN2A p.Arg99Pro (c.296G>C) pathogenic?

CDKN2A p.Arg99Pro (c.296G>C) is classified Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-18). AlphaMissense: likely pathogenic (0.9146); Absent from gnomAD v4.1; Associated with melanoma and neural system tumor syndrome.

What condition is associated with CDKN2A p.Arg99Pro (c.296G>C)?

CDKN2A p.Arg99Pro (c.296G>C) is associated with melanoma and neural system tumor syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Arg99Pro (c.296G>C) in the general population?

CDKN2A p.Arg99Pro (c.296G>C) is absent from gnomAD v4.1 (gnomAD).

How is Melanoma and neural system tumor syndrome inherited?

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

What do computational predictors say about CDKN2A p.Arg99Pro (c.296G>C)?

AlphaMissense predicts likely pathogenic (score 0.9146) — an in-silico prediction, not a clinical call.

CDKN2A p.Arg99Pro

c.296G>C · rs754806883 · VCV491572

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9146 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

melanoma and neural system tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.9146	likely pathogenic ✓ concordant with ClinVar
REVEL	0.365	indeterminate
SaProt	LLR -15.24	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	GERP -3
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	18.01	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.Arg99Pro
Coding: c.296G>C
MANE Select: NM_000077
dbSNP: rs754806883
Type: single nucleotide variant
Location: chr9:21971063 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 99: an α-helix; a UniProt-annotated variant site (in cmm2; loss of cdk4 binding); a UniProt-annotated variant site (in non-small cell lung carcinoma); a UniProt-annotated variant site (in); the 'disordered' region

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

melanoma and neural system tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma, cutaneous malignant, susceptibility to, 2 melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome familial melanoma

For Melanoma and neural system tumor syndrome (Orphanet):

Inheritance: Autosomal dominant, Unknown
Onset: Adult, Elderly

Similar variants

CDKN2A p.Arg99Leu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg99Trp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg99= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Arg99Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Arg99Gly Conflicting classifications of pathogenicity ★ ⚠ 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-arg99pro (accessed [today's date]).

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