Is CDKN2A p.Arg24Pro (c.71G>C) pathogenic?

CDKN2A p.Arg24Pro (c.71G>C) is classified Pathogenic/Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 23 submitters; last evaluated 2026-08-31). AlphaMissense: likely pathogenic (0.9136); Very rare (popmax 0.0011%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Arg24Pro (c.71G>C)?

CDKN2A p.Arg24Pro (c.71G>C) is associated with familial melanoma, melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Arg24Pro (c.71G>C) in the general population?

CDKN2A p.Arg24Pro (c.71G>C) is very rare (popmax 0.0011%, nfe) (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.Arg24Pro (c.71G>C)?

AlphaMissense predicts likely pathogenic (score 0.9136) — an in-silico prediction, not a clinical call.

CDKN2A p.Arg24Pro

c.71G>C · rs104894097 · VCV9415

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 23 submitters

AlphaMissense

likely pathogenic

0.9136 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.9136	likely pathogenic ✓ concordant with ClinVar
REVEL	0.402	indeterminate
SaProt	LLR -13.55	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 -1.7	GERP -0.71
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	20.6	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

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,470 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000808% 13/1,609,864 alleles · very rare

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.Arg24Pro
Coding: c.71G>C
MANE Select: NM_000077
dbSNP: rs104894097
Type: single nucleotide variant
Location: chr9:21974757 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 24: a UniProt-annotated variant site (in cmm2); a UniProt-annotated variant site (found in a patient with multiple primary melanoma; partial loss of cdk4 binding); 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, cutaneous malignant, susceptibility to, 2 melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Arg24Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg24Leu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val24Ala Uncertain significance ★★ same residue
CDKN2A p.Arg24= Benign/Likely benign ★★ same residue
CDKN2A p.Val24= Benign/Likely benign ★★ same residue
CDKN2A p.Arg24Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Arg24Trp Uncertain significance ★ ⚠ same residue
CDKN2A p.Val24Leu 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-arg24pro (accessed [today's date]).

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