Is CDKN2A p.Pro28Leu (c.83C>T) pathogenic?

CDKN2A p.Pro28Leu (c.83C>T) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-09). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Pro28Leu (c.83C>T)?

CDKN2A p.Pro28Leu (c.83C>T) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Pro28Leu (c.83C>T) in the general population?

CDKN2A p.Pro28Leu (c.83C>T) is absent from gnomAD v4.1 (gnomAD).

CDKN2A p.Pro28Leu

c.83C>T · rs1282190742 · VCV1426175

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

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	0.125	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -2.5
Overall
CADD	16.78	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.Pro28Leu
Coding: c.83C>T
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1282190742
Type: single nucleotide variant
Location: chr9:21994249 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 28: an α-helix; 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

Also linked: familial melanoma

Similar variants

CDKN2A p.Pro28Ser Uncertain significance ★★ same residue
CDKN2A p.Val28Leu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val28Met Uncertain significance ★★ ⚠ same residue
CDKN2A p.Pro28= Benign/Likely benign ★★ same residue
CDKN2A p.Pro28Arg Uncertain significance ★ same residue
CDKN2A p.Val28Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Pro28Thr Likely benign ★ same residue
CDKN2A c.150+1G>A 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-pro28leu (accessed [today's date]).

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