Is CDKN2A p.Leu16Arg (c.47T>G) pathogenic?

CDKN2A p.Leu16Arg (c.47T>G) is classified Pathogenic/Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-09-29). AlphaMissense: likely pathogenic (0.8404); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Leu16Arg (c.47T>G)?

CDKN2A p.Leu16Arg (c.47T>G) is associated with hereditary neoplastic syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Leu16Arg (c.47T>G) in the general population?

CDKN2A p.Leu16Arg (c.47T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Leu16Arg (c.47T>G)?

AlphaMissense predicts likely pathogenic (score 0.8404) — an in-silico prediction, not a clinical call.

CDKN2A p.Leu16Arg

c.47T>G · rs864622263 · VCV219815

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.8404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8404	likely pathogenic ✓ concordant with ClinVar
REVEL	0.57	indeterminate
SaProt	LLR -15.84	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	25.4	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 8.48e-05% European (non-Finnish) · 1/1,179,196 alleles

Overall 6.87e-05% 1/1,455,866 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.Leu16Arg
Coding: c.47T>G
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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

CDKN2A p.Leu16Pro 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-leu16arg (accessed [today's date]).

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