Is CDKN2A p.Glu33Val (c.98A>T) pathogenic?

CDKN2A p.Glu33Val (c.98A>T) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-12). AlphaMissense: ambiguous (0.3459); Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.Glu33Val (c.98A>T)?

CDKN2A p.Glu33Val (c.98A>T) is associated with familial melanoma (ClinVar).

How common is CDKN2A p.Glu33Val (c.98A>T) in the general population?

CDKN2A p.Glu33Val (c.98A>T) 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.Glu33Val (c.98A>T)?

AlphaMissense predicts ambiguous (score 0.3459) — an in-silico prediction, not a clinical call.

CDKN2A p.Glu33Val

c.98A>T · rs2489291265 · VCV2863240

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3459 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.3459	ambiguous
REVEL	0.45	indeterminate
SaProt	LLR -9.03	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.78	GERP -2
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

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.Glu33Val
Coding: c.98A>T
MANE Select: NM_000077
dbSNP: rs2489291265
Type: single nucleotide variant
Location: chr9:21974730 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 33: an α-helix; a UniProt-annotated variant site (in a biliary tract tumor); the 'interaction with cdk5rap3 and mdm2' 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.Glu33Gly Uncertain significance ★★ same residue
CDKN2A p.Glu33Lys Uncertain significance ★★ ⚠ same residue
CDKN2A p.Glu33Ter Likely pathogenic ★ ⚠ same residue
CDKN2A p.Glu33Gln Uncertain significance ★ ⚠ same residue
CDKN2A p.Glu33= Benign ★ 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-glu33val (accessed [today's date]).

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