Is CDKN2A p.Arg58= (c.174A>C) pathogenic?

CDKN2A p.Arg58= (c.174A>C) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-04-01). Rare (popmax 0.966%, afr); Associated with Li-Fraumeni syndrome.

What condition is associated with CDKN2A p.Arg58= (c.174A>C)?

CDKN2A p.Arg58= (c.174A>C) is associated with Li-Fraumeni syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Arg58= (c.174A>C) in the general population?

CDKN2A p.Arg58= (c.174A>C) is rare (popmax 0.966%, afr) (gnomAD).

How is Li-Fraumeni syndrome inherited?

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

CDKN2A p.Arg58=

c.174A>C · rs201208890 · VCV128200

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

rare (popmax 0.966%, afr)

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.133	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -4.1
Overall
CADD	2.263	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.966% African / African-American · 724/74,960 alleles

Filtering AF 0.908% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.884%

Overall 0.0519% 829/1,597,292 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.966%	104
Middle Eastern	0.102%	978
Remaining individualsnot grpmax-eligible	0.0804%	1,244
Admixed American	0.0384%	2,601
East Asian	0.00671%	14,903
South Asian	0.00441%	22,677
European (non-Finnish)	0.00161%	62,040

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.Arg58=
Coding: c.174A>C
MANE Select: NM_000077
dbSNP: rs201208890
Type: single nucleotide variant
Location: chr9:21971185 (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

Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma, cutaneous malignant, susceptibility to, 2 melanoma-pancreatic cancer syndrome familial pancreatic carcinoma hereditary neoplastic syndrome familial melanoma

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

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.Arg58Leu Uncertain significance ★ ⚠ same residue
CDKN2A p.Gln58Ter Conflicting classifications of pathogenicity ★ ⚠ 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-arg58 (accessed [today's date]).

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