Is CDKN2A p.Gln58Ter (c.172C>T) pathogenic?

CDKN2A p.Gln58Ter (c.172C>T) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-04). Ultra-rare (popmax 0.0165%, mid); Associated with familial melanoma.

What condition is associated with CDKN2A p.Gln58Ter (c.172C>T)?

CDKN2A p.Gln58Ter (c.172C>T) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Gln58Ter (c.172C>T) in the general population?

CDKN2A p.Gln58Ter (c.172C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Gln58Ter

c.172C>T · rs2131148082 · VCV1059393

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.4, phastCons 1
Overall
CADD	37.0	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 0.0165% Middle Eastern · 1/6,046 alleles

Overall 6.89e-05% 1/1,450,336 alleles · ultra-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.Gln58Ter
Coding: c.172C>T
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs2131148082
Type: single nucleotide variant
Location: chr9:21994160 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 58: an α-helix; 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: hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Arg58Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg58Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gln58Arg Uncertain significance ★★ same residue
CDKN2A p.Arg58= Benign/Likely benign ★★ same residue
CDKN2A p.Arg58Leu Uncertain significance ★ ⚠ same residue
CDKN2A p.Gln58= Likely benign ★ same residue
CDKN2A p.Arg58fs Pathogenic ★ same residue
CDKN2A p.Gln58fs Uncertain significance ★ 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-gln58ter (accessed [today's date]).

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