Is CDKN2A p.Leu50Pro (c.149T>C) pathogenic?

CDKN2A p.Leu50Pro (c.149T>C) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-05). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Leu50Pro (c.149T>C)?

CDKN2A p.Leu50Pro (c.149T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu50Pro (c.149T>C) in the general population?

CDKN2A p.Leu50Pro (c.149T>C) is absent from gnomAD v4.1 (gnomAD).

CDKN2A p.Leu50Pro

c.149T>C · rs1554659181 · VCV1773966

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.361	indeterminate
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	22.5	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.Leu50Pro
Coding: c.149T>C
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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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.Leu50Arg Uncertain significance ★★ same residue
CDKN2A p.Gln50His Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Gln50Lys Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gln50= 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-leu50pro (accessed [today's date]).

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