Is CDKN2A p.Leu55Val (c.163C>G) pathogenic?

CDKN2A p.Leu55Val (c.163C>G) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-04-25). Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Leu55Val (c.163C>G)?

CDKN2A p.Leu55Val (c.163C>G) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Leu55Val (c.163C>G) in the general population?

CDKN2A p.Leu55Val (c.163C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

CDKN2A p.Leu55Val

c.163C>G · rs1820527497 · VCV952988

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 0.00133%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.096	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -2.8
Overall
CADD	4.811	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,068 alleles

Overall 6.89e-05% 1/1,451,502 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.Leu55Val
Coding: c.163C>G
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1820527497
Type: single nucleotide variant
Location: chr9:21994169 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 55: 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.Leu55= Benign/Likely benign ★★ same residue
CDKN2A p.Gly55Asp Pathogenic ★ same residue
CDKN2A p.Gly55Ala Uncertain significance ★ ⚠ same residue
CDKN2A p.Gly55Arg Uncertain significance ★ ⚠ same residue
CDKN2A p.Gly55Val Uncertain significance ★ ⚠ same residue
CDKN2A p.Leu55fs Uncertain significance ★ same residue
CDKN2A p.Gly55= Pathogenic ★ 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-leu55val (accessed [today's date]).

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