Is CDKN2A p.Val59Gly (c.176T>G) pathogenic?

CDKN2A p.Val59Gly (c.176T>G) is classified Pathogenic/Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-11). AlphaMissense: likely pathogenic (0.6413); Ultra-rare (popmax 0.017%, mid); Associated with familial melanoma.

What condition is associated with CDKN2A p.Val59Gly (c.176T>G)?

CDKN2A p.Val59Gly (c.176T>G) is associated with familial melanoma, melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Val59Gly (c.176T>G) in the general population?

CDKN2A p.Val59Gly (c.176T>G) is ultra-rare (popmax 0.017%, mid) (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.Val59Gly (c.176T>G)?

AlphaMissense predicts likely pathogenic (score 0.6413) — an in-silico prediction, not a clinical call.

CDKN2A p.Val59Gly

c.176T>G · rs104894099 · VCV9423

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

AlphaMissense

likely pathogenic

0.6413 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.6413	likely pathogenic ✓ concordant with ClinVar
REVEL	0.65	pathogenic-leaning
SaProt	LLR -12.69	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 7.9	GERP 0.9, phastCons 0.99
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.0	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

Grpmax group 0.017% Middle Eastern · 1/5,888 alleles

Overall 0.000208% 3/1,444,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,888
Admixed American	0.00167%	59,814
Remaining individualsnot grpmax-eligible	0.00161%	62,200

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.Val59Gly
Coding: c.176T>G
MANE Select: NM_000077
dbSNP: rs104894099
Type: single nucleotide variant
Location: chr9:21971183 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 59: an α-helix; a UniProt-annotated variant site (in cmm2); the 'interaction with cdk5rap3 and mdm2' region; 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

Also linked: melanoma, cutaneous malignant, susceptibility to, 2 melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Pro59Leu Uncertain significance ★★ same residue
CDKN2A p.Val59Ala Uncertain significance ★★ same residue
CDKN2A p.Val59Met Uncertain significance ★★ ⚠ same residue
CDKN2A p.Pro59= Likely benign ★★ same residue
CDKN2A p.Val59= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Val59Glu Uncertain significance ★ ⚠ same residue
CDKN2A p.Val59Leu Uncertain significance ★ ⚠ same residue
CDKN2A p.Val59fs Pathogenic ★ 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-val59gly (accessed [today's date]).

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