Is CDKN2A p.Leu63fs (c.182_185dup) pathogenic?

CDKN2A p.Leu63fs (c.182185dup) is classified Likely pathogenic in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-28). Absent from gnomAD; Associated with melanoma and neural system tumor syndrome.

What condition is associated with CDKN2A p.Leu63fs (c.182_185dup)?

CDKN2A p.Leu63fs (c.182_185dup) is associated with melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Leu63fs (c.182_185dup) in the general population?

CDKN2A p.Leu63fs (c.182_185dup) is absent from gnomAD (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.

CDKN2A p.Leu63fs

c.182_185dup · rs2489276684 · VCV2680554

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

melanoma and neural system tumor syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.69	GERP -1.9, phastCons 0.009

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDKN2A
Protein: p.Leu63fs
Coding: c.182_185dup
MANE Select: NM_000077
dbSNP: rs2489276684
Type: Duplication
Location: chr9:21971173 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 63: an α-helix; the 'interaction with cdk5rap3 and mdm2' region; 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

For Melanoma and neural system tumor syndrome (Orphanet):

Inheritance: Autosomal dominant, Unknown
Onset: Adult, Elderly

Similar variants

CDKN2A p.Arg112_Leu113insArg Pathogenic ★★ same condition
CDKN2A p.Leu121fs Pathogenic/Likely pathogenic ★★ same condition
CDKN2A p.Arg63Ile Uncertain significance ★★ same residue
CDKN2A p.Arg63Lys Uncertain significance ★★ same residue
CDKN2A p.Thr137fs Uncertain significance ★★ same condition
CDKN2A p.Val82fs Likely pathogenic ★ same condition
CDKN2A p.Arg63= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Arg63del 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-leu63fs (accessed [today's date]).

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