Is CDKN2A p.Arg46fs (c.135dup) pathogenic?

CDKN2A p.Arg46fs (c.135dup) is classified Pathogenic in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-14). No gnomAD frequency available for this variant; Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Arg46fs (c.135dup)?

CDKN2A p.Arg46fs (c.135dup) is associated with melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Arg46fs (c.135dup) in the general population?

CDKN2A p.Arg46fs (c.135dup) is no gnomAD frequency available for this variant (gnomAD).

CDKN2A p.Arg46fs

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.135dup · rs2489290573 · VCV2449063

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

melanoma-pancreatic cancer 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 1 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.88	GERP 2, phastCons 0.086

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.Arg46fs
Coding: c.135dup
MANE Select: NM_000077
dbSNP: rs2489290573
Type: Duplication
Location: chr9:21974692 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 46: 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.Arg46Gln Uncertain significance ★★ same residue
CDKN2A p.Arg46Trp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val46Met Uncertain significance ★★ same residue
CDKN2A p.Val46= Benign/Likely benign ★★ same residue
CDKN2A p.Arg46= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Arg46Pro Uncertain significance ★ ⚠ same residue
CDKN2A p.Val46Ala Uncertain significance ★ same residue
CDKN2A p.Val46Gly 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-arg46fs (accessed [today's date]).

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