Is CDKN2A p.Arg80Ter (c.238C>T) pathogenic?

CDKN2A p.Arg80Ter (c.238C>T) is classified Pathogenic/Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 9 submitters; last evaluated 2023-07-19). Very rare (popmax 8.48e-05%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Arg80Ter (c.238C>T)?

CDKN2A p.Arg80Ter (c.238C>T) is associated with familial melanoma, melanoma, cutaneous malignant, susceptibility to, 2, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Arg80Ter (c.238C>T) in the general population?

CDKN2A p.Arg80Ter (c.238C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Arg80Ter

c.238C>T · rs121913388 · VCV9409

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 3
REVEL	0.48	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.58	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.3	GERP 0.11, phastCons 0.059
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,498 alleles

Overall 6.89e-05% 1/1,451,466 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.Arg80Ter
Coding: c.238C>T
MANE Select: NM_000077
dbSNP: rs121913388
Type: single nucleotide variant
Location: chr9:21971121 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 80: a UniProt-annotated variant site (in a head and neck tumor); a UniProt-annotated variant site (in cmm2; loss of cdk4 binding); 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 hereditary neoplastic syndrome lip and oral cavity carcinoma

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Arg80Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg80Pro Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg80Gly Uncertain significance ★ ⚠ same residue
CDKN2A p.Arg80= Likely benign ★ same residue
CDKN2A p.Arg80fs Pathogenic ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A 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-arg80ter (accessed [today's date]).

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