Is CDKN2A p.Leu45= (c.135C>T) pathogenic?

CDKN2A p.Leu45= (c.135C>T) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-12). Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.Leu45= (c.135C>T)?

CDKN2A p.Leu45= (c.135C>T) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu45= (c.135C>T) in the general population?

CDKN2A p.Leu45= (c.135C>T) is absent from gnomAD v4.1 (gnomAD).

How is Familial melanoma inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

CDKN2A p.Leu45=

c.135C>T · rs766676234 · VCV1116520

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.061	GERP -1.3, phastCons 0.001
Overall
CADD	12.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN2A
Protein: p.Leu45=
Coding: c.135C>T
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs766676234
Type: single nucleotide variant
Location: chr9:21994197 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 45: a β-strand; the 'interaction with cdk5rap3 and mdm2' region

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDKN2A p.Gly45Arg Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly45Cys Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly45Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Leu45Val Uncertain significance ★★ same residue
CDKN2A p.Gly45Ala Uncertain significance ★ ⚠ same residue
CDKN2A p.Leu45Ile Uncertain significance ★ same residue
CDKN2A p.Gly45del Uncertain significance ★ same residue
CDKN2A p.Leu45fs Conflicting classifications of pathogenicity ★ ⚠ 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-leu45 (accessed [today's date]).

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