Is CDKN2A p.Pro81fs (c.240_253del) pathogenic?

CDKN2A p.Pro81fs (c.240253del) is classified Pathogenic in CDKN2A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-21). Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Pro81fs (c.240_253del)?

CDKN2A p.Pro81fs (c.240_253del) is associated with hereditary neoplastic syndrome, melanoma-pancreatic cancer syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Pro81fs (c.240_253del) in the general population?

CDKN2A p.Pro81fs (c.240_253del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

CDKN2A p.Pro81fs

c.240_253del · rs730881675 · VCV182412

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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

Conditions

hereditary neoplastic 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 12	GERP 2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,586 alleles

Overall 6.89e-05% 1/1,452,314 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.Pro81fs
Coding: c.240_253del
MANE Select: NM_000077
dbSNP: rs730881675
Type: Deletion
Location: chr9:21971106 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 81: an α-helix; a UniProt-annotated variant site (in some patients with melanoma; impairs the function); a UniProt-annotated variant site (in cmm2; loss of cdk4 binding); the 'disordered' 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-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.Pro81Leu Likely pathogenic ★★ same residue
CDKN2A p.Pro81= Uncertain significance ★ same residue
CDKN2A p.Pro81Ala Uncertain significance ★ same residue
CDKN2A p.Pro81Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Pro81Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Pro81Thr Uncertain significance ★ ⚠ same residue
CDKN2A c.193+1del Likely pathogenic ★★ same condition
CDKN2A c.457+1_457+10del Pathogenic/Likely pathogenic ★★ same condition

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-pro81fs (accessed [today's date]).

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