Is CDKN2A p.Ile145fs (c.433dup) pathogenic?

CDKN2A p.Ile145fs (c.433dup) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ile145fs (c.433dup)?

CDKN2A p.Ile145fs (c.433dup) is associated with hereditary neoplastic syndrome (ClinVar).

CDKN2A p.Ile145fs

c.433dup · VCV3830993

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (2 of 3, 23 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.1	GERP -1.8

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

Variant & gene context

Gene: CDKN2A
Protein: p.Ile145fs
Coding: c.433dup
MANE Select: NM_000077
Type: Duplication
Location: chr9:21970925 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 145: a β-strand

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

Similar variants

CDKN2A p.Ile145Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Ile145Arg Likely benign ★ same residue
CDKN2A p.Ile145Leu Likely benign ★ same residue
CDKN2A p.Arg112_Leu113insArg Pathogenic ★★ same condition
CDKN2A p.Arg46fs Pathogenic ★★ same condition
CDKN2A p.Ser43Ter Pathogenic ★★ same condition
CDKN2A p.Ser8fs Pathogenic ★★ same condition
CDKN2A p.Ala73_Asp74insAla Uncertain significance ★★ 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-ile145fs (accessed [today's date]).

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