Is CDKN2A p.Arg51= (c.153G>A) pathogenic?

CDKN2A p.Arg51= (c.153G>A) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-12). Very rare (popmax 0.000339%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Arg51= (c.153G>A)?

CDKN2A p.Arg51= (c.153G>A) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Arg51= (c.153G>A) in the general population?

CDKN2A p.Arg51= (c.153G>A) is very rare (popmax 0.000339%, 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.Arg51=

c.153G>A · rs773369448 · VCV1099059

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

familial melanoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.6, phastCons 1
Overall
CADD	15.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,888 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000344% 5/1,452,808 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,376
European (non-Finnish)grpmax	0.000339%	294,972

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg51=
Coding: c.153G>A
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs773369448
Type: single nucleotide variant
Location: chr9:21994179 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 51: an α-helix; the 'interaction with cdk5rap3 and mdm2' 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-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.Val51Ile Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val51Phe Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg51Lys Uncertain significance ★ same residue
CDKN2A p.Arg51Thr Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Val51Leu Uncertain significance ★ ⚠ same residue
CDKN2A p.Val51= Likely benign ★ same residue
CDKN2A p.Arg51fs Uncertain significance ★ same residue
CDKN2A c.150+1G>A 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-arg51 (accessed [today's date]).

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