Is CDKN2A p.Leu50Arg (c.149T>G) pathogenic?

CDKN2A p.Leu50Arg (c.149T>G) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-29). Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.Leu50Arg (c.149T>G)?

CDKN2A p.Leu50Arg (c.149T>G) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu50Arg (c.149T>G) in the general population?

CDKN2A p.Leu50Arg (c.149T>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.Leu50Arg

c.149T>G · rs1554659181 · VCV532282

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 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.
REVEL	0.234	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2.3, phastCons 0.28
Overall
CADD	20.3	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.Leu50Arg
Coding: c.149T>G
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1554659181
Type: single nucleotide variant
Location: chr9:21994183 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 50: an α-helix; a UniProt-annotated variant site (in cmm2); 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: hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Gln50Arg Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gln50Pro Likely pathogenic ★★ same residue
CDKN2A p.Gln50Ter Pathogenic ★★ same residue
CDKN2A p.Gln50Leu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gln50= Uncertain significance ★ same residue
CDKN2A p.Gln50His Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Leu50Pro Uncertain significance ★ same residue
CDKN2A p.Gln50Lys Uncertain significance ★★ ⚠ 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-leu50arg (accessed [today's date]).

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