Is CDKN2A p.Gly111Val (c.332G>T) pathogenic?

CDKN2A p.Gly111Val (c.332G>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-27). AlphaMissense: likely pathogenic (0.8854); Very rare (popmax 6.88e-05%); Associated with melanoma and neural system tumor syndrome.

What condition is associated with CDKN2A p.Gly111Val (c.332G>T)?

CDKN2A p.Gly111Val (c.332G>T) is associated with melanoma and neural system tumor syndrome, hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Gly111Val (c.332G>T) in the general population?

CDKN2A p.Gly111Val (c.332G>T) is very rare (popmax 6.88e-05%) (gnomAD).

How is Melanoma and neural system tumor syndrome inherited?

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

What do computational predictors say about CDKN2A p.Gly111Val (c.332G>T)?

AlphaMissense predicts likely pathogenic (score 0.8854) — an in-silico prediction, not a clinical call.

CDKN2A p.Gly111Val

c.332G>T · rs2131093568 · VCV1487529

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.88e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

melanoma and neural system tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.8854	likely pathogenic
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -15.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 6.88e-05%

Overall 6.88e-05% 1/1,454,290 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.Gly111Val
Coding: c.332G>T
MANE Select: NM_000077
dbSNP: rs2131093568
Type: single nucleotide variant
Location: chr9:21971027 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 111: a β-strand; the 'disordered' region

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

Disease context

melanoma and neural system tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome familial melanoma

For Melanoma and neural system tumor syndrome (Orphanet):

Inheritance: Autosomal dominant, Unknown
Onset: Adult, Elderly

Similar variants

CDKN2A p.Gly111= Uncertain significance ★★ same residue
CDKN2A p.Gly111Arg Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly111Asp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly111Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly111Cys Uncertain significance ★ ⚠ same residue
CDKN2A p.Gly111fs Pathogenic ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G 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-gly111val (accessed [today's date]).

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