Is CDKN2A p.Arg128= (c.384G>A) pathogenic?

CDKN2A p.Arg128= (c.384G>A) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0267%, amr); Associated with familial melanoma.

What condition is associated with CDKN2A p.Arg128= (c.384G>A)?

CDKN2A p.Arg128= (c.384G>A) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Arg128= (c.384G>A) in the general population?

CDKN2A p.Arg128= (c.384G>A) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

How is Familial melanoma inherited?

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

CDKN2A p.Arg128=

c.384G>A · rs199901898 · VCV184241

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

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 -1.7	GERP 1.1
Overall
CADD	10.66	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/60,014 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.014% 226/1,611,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,751
European (non-Finnish)	0.0169%	5,900
Remaining individualsnot grpmax-eligible	0.0128%	7,800
African / African-American	0.00267%	37,470

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.Arg128=
Coding: c.384G>A
MANE Select: NM_000077
dbSNP: rs199901898
Type: single nucleotide variant
Location: chr9:21970975 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 128: an α-helix; 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-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.Arg128Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg128Pro Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg128Trp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg128Gly Uncertain significance ★ ⚠ same residue
CDKN2A p.Arg128Leu Uncertain significance ★ ⚠ same residue
CDKN2A p.Arg128fs Likely pathogenic ★★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G 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-arg128 (accessed [today's date]).

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