Is CDKN2A p.Leu16Pro (c.47T>C) pathogenic?

CDKN2A p.Leu16Pro (c.47T>C) is classified Pathogenic/Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.8704); Very rare (popmax 0.000254%, nfe); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Leu16Pro (c.47T>C)?

CDKN2A p.Leu16Pro (c.47T>C) is associated with melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Leu16Pro (c.47T>C) in the general population?

CDKN2A p.Leu16Pro (c.47T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Leu16Pro (c.47T>C)?

AlphaMissense predicts likely pathogenic (score 0.8704) — an in-silico prediction, not a clinical call.

CDKN2A p.Leu16Pro

Q: How is Familial atypical multiple mole melanoma syndrome inherited?

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

c.47T>C · rs864622263 · VCV649266

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

melanoma-pancreatic cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.8704	likely pathogenic ✓ concordant with ClinVar
REVEL	0.571	indeterminate
SaProt	LLR -18.16	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 11	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	25.2	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 0.000254% European (non-Finnish) · 3/1,179,196 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000206% 3/1,455,866 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.Leu16Pro
Coding: c.47T>C
MANE Select: NM_000077
dbSNP: rs864622263
Type: single nucleotide variant
Location: chr9:21974781 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 16: an α-helix; a UniProt-annotated variant site (in a biliary tract tumor and a familial melanoma); the 'interaction with cdk5rap3 and mdm2' region

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

Disease context

melanoma-pancreatic cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial melanoma

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Leu16Arg Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gly16Arg Uncertain significance ★★ same residue
CDKN2A p.Gly16Asp Uncertain significance ★★ same residue
CDKN2A p.Gly16Ser Uncertain significance ★★ same residue
CDKN2A p.Leu16Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly16= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Gly16Val Uncertain significance ★ same residue
CDKN2A p.Leu16= Benign ★ 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-leu16pro (accessed [today's date]).

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