Is CDKN2A p.Cys72= (c.216C>T) pathogenic?

CDKN2A p.Cys72= (c.216C>T) is classified Likely benign in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). Very rare (popmax 0.00226%, eas); Associated with familial melanoma.

What condition is associated with CDKN2A p.Cys72= (c.216C>T)?

CDKN2A p.Cys72= (c.216C>T) is associated with familial melanoma (ClinVar).

How common is CDKN2A p.Cys72= (c.216C>T) in the general population?

CDKN2A p.Cys72= (c.216C>T) is very rare (popmax 0.00226%, eas) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Cys72=

c.216C>T · rs1563889729 · VCV1086966

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.166	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.21, phastCons 0.79
Overall
CADD	11.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00226% East Asian · 1/44,338 alleles

Overall 6.94e-05% 1/1,441,396 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.Cys72=
Coding: c.216C>T
MANE Select: NM_000077
dbSNP: rs1563889729
Type: single nucleotide variant
Location: chr9:21971143 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 72: a UniProt-annotated variant site (in an esophagus 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.Cys72Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Cys72Gly Uncertain significance ★ ⚠ same residue
CDKN2A p.Cys72Phe Uncertain significance ★★ ⚠ same residue
CDKN2A p.Cys72Tyr Uncertain significance ★ ⚠ 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
CDKN2A c.151-2A>G Pathogenic/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-cys72 (accessed [today's date]).

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