Is CDKN2A p.Leu6Ser (c.17T>C) pathogenic?

CDKN2A p.Leu6Ser (c.17T>C) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-17). Very rare (popmax 6.23e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Leu6Ser (c.17T>C)?

CDKN2A p.Leu6Ser (c.17T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu6Ser (c.17T>C) in the general population?

CDKN2A p.Leu6Ser (c.17T>C) is very rare (popmax 6.23e-05%) (gnomAD).

CDKN2A p.Leu6Ser

c.17T>C · rs2489328317 · VCV2563900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 6.23e-05%)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.701	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.4, phastCons 0.96
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.23e-05%

Overall 6.23e-05% 1/1,606,002 alleles · very rare exomes 1/1,453,846 · genomes 0/152,156 · joint denominator

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.Leu6Ser
Coding: c.17T>C
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs2489328317
Type: single nucleotide variant
Location: chr9:21994315 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 6: a β-strand; 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.Gly6Ala Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly6Arg Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly6Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly6Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Leu6= Likely benign ★ same residue
CDKN2A p.Gly6= Likely benign ★ same residue
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>C 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-leu6ser (accessed [today's date]).

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