Is CDKN2A p.Ala36fs (c.106del) pathogenic?

CDKN2A p.Ala36fs (c.106del) is classified Pathogenic in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-14). Very rare (popmax 0.00168%, amr); Associated with melanoma-pancreatic cancer syndrome.

What condition is associated with CDKN2A p.Ala36fs (c.106del)?

CDKN2A p.Ala36fs (c.106del) is associated with melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Ala36fs (c.106del) in the general population?

CDKN2A p.Ala36fs (c.106del) is very rare (popmax 0.00168%, amr) (gnomAD).

CDKN2A p.Ala36fs

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.106del · rs398123152 · VCV1171238

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

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 -2.2	GERP -3.1
Region caveats
Repeat context	tandem	GCAGCGCCCCCACCTCCA simple repeat · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,398 alleles

Overall 6.89e-05% 1/1,450,760 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.Ala36fs
Coding: c.106del
MANE Select: NM_000077
dbSNP: rs398123152
Type: Deletion
Location: chr9:21974722 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 36: 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

For Familial atypical multiple mole melanoma syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

CDKN2A p.Ala36Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala36Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala36Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala36= Benign/Likely benign ★★ same residue
CDKN2A p.Ala36Glu Uncertain significance ★ same residue
CDKN2A c.193+1del Likely pathogenic ★★ same condition
CDKN2A c.457+1_457+10del Pathogenic/Likely pathogenic ★★ same condition
CDKN2A p.Ala76fs 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-ala36fs (accessed [today's date]).

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