Is CDKN2A p.Arg128Pro (c.383G>C) pathogenic?

CDKN2A p.Arg128Pro (c.383G>C) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.6461); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Arg128Pro (c.383G>C)?

CDKN2A p.Arg128Pro (c.383G>C) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Arg128Pro (c.383G>C) in the general population?

CDKN2A p.Arg128Pro (c.383G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDKN2A p.Arg128Pro (c.383G>C)?

AlphaMissense predicts likely pathogenic (score 0.6461) — an in-silico prediction, not a clinical call.

CDKN2A p.Arg128Pro

c.383G>C · rs971657556 · VCV483344

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6461	likely pathogenic
REVEL	0.66	pathogenic-leaning
SaProt	LLR -14.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.9	GERP -4
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	13.76	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 6.86e-05% 1/1,458,694 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.Arg128Pro
Coding: c.383G>C
MANE Select: NM_000077
dbSNP: rs971657556
Type: single nucleotide variant
Location: chr9:21970976 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial melanoma

Similar variants

CDKN2A p.Arg128Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg128Trp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg128= Benign/Likely benign ★★ 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-arg128pro (accessed [today's date]).

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