Is CDKN2A p.Arg128Trp (c.382C>T) pathogenic?

CDKN2A p.Arg128Trp (c.382C>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-23). AlphaMissense: likely benign (0.1984); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Arg128Trp (c.382C>T)?

CDKN2A p.Arg128Trp (c.382C>T) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Arg128Trp (c.382C>T) in the general population?

CDKN2A p.Arg128Trp (c.382C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Arg128Trp (c.382C>T)?

AlphaMissense predicts likely benign (score 0.1984) — an in-silico prediction, not a clinical call.

CDKN2A p.Arg128Trp

c.382C>T · rs1563888826 · VCV575361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1984 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,611,026)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1984	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -9.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.7	GERP -4
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	13.78	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

No allele count reported in gnomAD v4.1 (AN 1,611,026). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDKN2A
Protein: p.Arg128Trp
Coding: c.382C>T
MANE Select: NM_000077
dbSNP: rs1563888826
Type: single nucleotide variant
Location: chr9:21970977 (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.Arg128Pro 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-arg128trp (accessed [today's date]).

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