Is CDKN2A p.Arg87Trp (c.259C>T) pathogenic?

CDKN2A p.Arg87Trp (c.259C>T) is classified Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-31). AlphaMissense: likely pathogenic (0.6316); Very rare (popmax 0.0022%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Arg87Trp (c.259C>T)?

CDKN2A p.Arg87Trp (c.259C>T) is associated with hereditary neoplastic syndrome, melanoma and neural system tumor syndrome, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Arg87Trp (c.259C>T) in the general population?

CDKN2A p.Arg87Trp (c.259C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CDKN2A p.Arg87Trp (c.259C>T)?

AlphaMissense predicts likely pathogenic (score 0.6316) — an in-silico prediction, not a clinical call.

CDKN2A p.Arg87Trp

c.259C>T · rs749714198 · VCV406707

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.6316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6316	likely pathogenic ✓ concordant with ClinVar
REVEL	0.555	indeterminate
SaProt	LLR -13.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP 0.16, phastCons 0.88
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,006 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000374% 6/1,604,616 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,503
European (non-Finnish)	0.000339%	294,897

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.Arg87Trp
Coding: c.259C>T
MANE Select: NM_000077
dbSNP: rs749714198
Type: single nucleotide variant
Location: chr9:21971100 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 87: an α-helix; a UniProt-annotated variant site (in cmm2; impairs the function); a UniProt-annotated variant site (in cmm2; partial loss of cdk4 binding); 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: melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome familial meningioma familial melanoma

Similar variants

CDKN2A p.Arg87Pro Pathogenic ★★ same residue
CDKN2A p.Arg87Leu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg87= Uncertain significance ★ same residue
CDKN2A p.Arg87Gln Uncertain significance ★ ⚠ same residue
CDKN2A p.Arg87Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A 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-arg87trp (accessed [today's date]).

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