Is CDKN2A p.Leu113= (c.339G>A) pathogenic?

CDKN2A p.Leu113= (c.339G>A) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-02). Very rare (popmax 0.000678%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Leu113= (c.339G>A)?

CDKN2A p.Leu113= (c.339G>A) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu113= (c.339G>A) in the general population?

CDKN2A p.Leu113= (c.339G>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Leu113=

c.339G>A · rs575031539 · VCV142725

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.29	benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.39	GERP -2.2, phastCons 0.99
Overall
CADD	11.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,672 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000498% 8/1,607,312 alleles · very rare exomes 8/1,454,934 · genomes 0/152,378 · joint denominator

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.Leu113=
Coding: c.339G>A
MANE Select: NM_000077
dbSNP: rs575031539
Type: single nucleotide variant
Location: chr9:21971020 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 113: the 'disordered' region; a UniProt-annotated variant site (in)

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: hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Leu113Pro Uncertain significance ★★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A Pathogenic ★★ same condition
CDKN2A c.151-1G>C Pathogenic ★★ same condition
CDKN2A c.151-1G>T Pathogenic/Likely pathogenic ★★ same condition
CDKN2A c.151-2A>G Pathogenic/Likely pathogenic ★★ same condition
CDKN2A c.193+1G>A 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-leu113 (accessed [today's date]).

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