Is CDKN2A p.Leu64= (c.190C>T) pathogenic?

CDKN2A p.Leu64= (c.190C>T) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-03-04). Very rare (popmax 8.49e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Leu64= (c.190C>T)?

CDKN2A p.Leu64= (c.190C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu64= (c.190C>T) in the general population?

CDKN2A p.Leu64= (c.190C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

CDKN2A p.Leu64=

c.190C>T · rs2131096124 · VCV1332610

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.398	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2.1, phastCons 1
Overall
CADD	14.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,924 alleles

Overall 6.93e-05% 1/1,443,436 alleles · very rare

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.Leu64=
Coding: c.190C>T
MANE Select: NM_000077
dbSNP: rs2131096124
Type: single nucleotide variant
Location: chr9:21971169 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 64: an α-helix; the 'interaction with cdk5rap3 and mdm2' region; the 'disordered' 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.Leu64Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Pro64= Uncertain significance ★★ same residue
CDKN2A p.Pro64Arg Uncertain significance ★★ same residue
CDKN2A p.Pro64Gln Uncertain significance ★★ same residue
CDKN2A p.Pro64Leu Uncertain significance ★★ same residue
CDKN2A p.Leu64Pro Uncertain significance ★ ⚠ same residue
CDKN2A p.Leu64fs Pathogenic ★★ same residue
CDKN2A p.Pro64Thr 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-leu64 (accessed [today's date]).

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