Is CDKN2A p.Leu16Gln (c.47T>A) pathogenic?

CDKN2A p.Leu16Gln (c.47T>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.922); Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.Leu16Gln (c.47T>A)?

CDKN2A p.Leu16Gln (c.47T>A) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu16Gln (c.47T>A) in the general population?

CDKN2A p.Leu16Gln (c.47T>A) is absent from gnomAD v4.1 (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.Leu16Gln (c.47T>A)?

AlphaMissense predicts likely pathogenic (score 0.922) — an in-silico prediction, not a clinical call.

CDKN2A p.Leu16Gln

c.47T>A · rs864622263 · VCV463509

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.922 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.922	likely pathogenic · top 10% in CDKN2A
REVEL	0.543	indeterminate
SaProt	LLR -16.56	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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Leu16Gln
Coding: c.47T>A
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

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Leu16Arg Pathogenic/Likely pathogenic ★★ same residue
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.Gly16= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Gly16Val Uncertain significance ★ same residue
CDKN2A p.Leu16fs Pathogenic ★★ 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-leu16gln (accessed [today's date]).

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