Is CDKN2A p.Leu45Val (c.133C>G) pathogenic?

CDKN2A p.Leu45Val (c.133C>G) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-09). Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.Leu45Val (c.133C>G)?

CDKN2A p.Leu45Val (c.133C>G) is associated with familial melanoma, melanoma and neural system tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu45Val (c.133C>G) in the general population?

CDKN2A p.Leu45Val (c.133C>G) 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.Leu45Val

c.133C>G · rs1554659193 · VCV483346

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,606,554)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.304	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.61, phastCons 1
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,606,554). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDKN2A
Protein: p.Leu45Val
Coding: c.133C>G
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1554659193
Type: single nucleotide variant
Location: chr9:21994199 (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 and neural system tumor 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.Leu45= Benign/Likely benign ★★ 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-leu45val (accessed [today's date]).

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