Is CDKN2A p.Glu69Ala (c.206A>C) pathogenic?

CDKN2A p.Glu69Ala (c.206A>C) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-08). AlphaMissense: likely benign (0.2904); Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.Glu69Ala (c.206A>C)?

CDKN2A p.Glu69Ala (c.206A>C) is associated with familial melanoma (ClinVar).

How common is CDKN2A p.Glu69Ala (c.206A>C) in the general population?

CDKN2A p.Glu69Ala (c.206A>C) is absent from gnomAD v4.1 (gnomAD).

How is Familial melanoma inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKN2A p.Glu69Ala (c.206A>C)?

AlphaMissense predicts likely benign (score 0.2904) — an in-silico prediction, not a clinical call.

CDKN2A p.Glu69Ala

c.206A>C · rs372670098 · VCV2891892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2904 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.2904	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Glu69Ala
Coding: c.206A>C
MANE Select: NM_000077
dbSNP: rs372670098
Type: single nucleotide variant
Location: chr9:21971153 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 69: a UniProt-annotated variant site (in melanoma; loss of cdk4 binding); a UniProt-annotated variant site (found in some patients with melanoma; partial loss of cdk4 binding); a UniProt-annotated variant site (in a bladder tumor); a UniProt-annotated variant site (in a lung tumor); the 'disordered' region

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDKN2A p.Glu69Asp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Glu69= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Glu69Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Glu69Lys Uncertain significance ★ ⚠ same residue
CDKN2A p.Glu69Ter Pathogenic ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A 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-glu69ala (accessed [today's date]).

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