Is CDKN2A p.Ile27Leu (c.79A>C) pathogenic?

CDKN2A p.Ile27Leu (c.79A>C) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-02-02). Very rare (popmax 0.00331%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ile27Leu (c.79A>C)?

CDKN2A p.Ile27Leu (c.79A>C) is associated with hereditary neoplastic syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Ile27Leu (c.79A>C) in the general population?

CDKN2A p.Ile27Leu (c.79A>C) is very rare (popmax 0.00331%, nfe) (gnomAD).

CDKN2A p.Ile27Leu

c.79A>C · rs1057517575 · VCV371881

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.185	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -3.1
Overall
CADD	13.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% European (non-Finnish) · 39/1,178,772 alleles

Filtering AF 0.00248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00243% 39/1,606,486 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.Ile27Leu
Coding: c.79A>C
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1057517575
Type: single nucleotide variant
Location: chr9:21994253 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 27: 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: melanoma, cutaneous malignant, susceptibility to, 2 melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.Glu27Ter Pathogenic ★★ same residue
CDKN2A p.Glu27Ala Uncertain significance ★★ ⚠ same residue
CDKN2A p.Glu27Asp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Glu27Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ile27Met Uncertain significance ★★ same residue
CDKN2A p.Glu27= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Glu27Gln Uncertain significance ★ ⚠ same residue
CDKN2A p.Glu27Lys 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-ile27leu (accessed [today's date]).

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