Is CDKN2A p.Ser140fs (c.419_425del) pathogenic?

CDKN2A p.Ser140fs (c.419425del) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ser140fs (c.419_425del)?

CDKN2A p.Ser140fs (c.419_425del) is associated with hereditary neoplastic syndrome (ClinVar).

CDKN2A p.Ser140fs

c.419_425del · VCV3830995

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, 32 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 -3	GERP -2.7

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

Variant & gene context

Gene: CDKN2A
Protein: p.Ser140fs
Coding: c.419_425del
MANE Select: NM_000077
Type: Deletion
Location: chr9:21970934 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 140: a modified residue (phosphoserine)

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.Ser140Asn Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ser140= Likely benign ★ same residue
CDKN2A p.Ser140Arg Likely benign ★ same residue
CDKN2A c.193+1del Likely pathogenic ★★ same condition
CDKN2A c.457+1_457+10del Pathogenic/Likely pathogenic ★★ same condition
CDKN2A p.Ala36fs Pathogenic ★★ same condition
CDKN2A p.Ala76fs Pathogenic/Likely pathogenic ★★ same condition
CDKN2A p.Asn71fs 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-ser140fs (accessed [today's date]).

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