Is CDKN2A p.Asp84Ala (c.251A>C) pathogenic?

CDKN2A p.Asp84Ala (c.251A>C) is classified Pathogenic/Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-26). AlphaMissense: likely pathogenic (0.8398); Very rare (popmax 0.000593%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Asp84Ala (c.251A>C)?

CDKN2A p.Asp84Ala (c.251A>C) is associated with familial melanoma, melanoma and neural system tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Asp84Ala (c.251A>C) in the general population?

CDKN2A p.Asp84Ala (c.251A>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

How is Familial melanoma inherited?

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

What do computational predictors say about CDKN2A p.Asp84Ala (c.251A>C)?

AlphaMissense predicts likely pathogenic (score 0.8398) — an in-silico prediction, not a clinical call.

CDKN2A p.Asp84Ala

c.251A>C · rs587782792 · VCV142882

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.8398	likely pathogenic ✓ concordant with ClinVar
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	26.1	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 0.000593% European (non-Finnish) · 7/1,179,570 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000436% 7/1,604,496 alleles · very rare exomes 7/1,452,176 · genomes 0/152,320 · joint denominator

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.Asp84Ala
Coding: c.251A>C
MANE Select: NM_000077
dbSNP: rs587782792
Type: single nucleotide variant
Location: chr9:21971108 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 84: an α-helix; a UniProt-annotated variant site (in a bladder tumor); a UniProt-annotated variant site (in non-small cell lung carcinoma); a UniProt-annotated variant site (in an esophagus tumor; also found in head and neck tumor; also found in a lung tumor); a UniProt-annotated variant site (in cmm2; also found in a lung tumor and a prostate tumor); 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 and neural system tumor 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.Asp84Asn Likely pathogenic ★★ same residue
CDKN2A p.Asp84= Uncertain significance ★★ same residue
CDKN2A p.Asp84Val Likely pathogenic ★ same residue
CDKN2A p.Asp84Glu Uncertain significance ★ ⚠ same residue
CDKN2A p.Asp84His Uncertain significance ★ ⚠ same residue
CDKN2A p.Asp84Tyr Conflicting classifications of pathogenicity ★ ⚠ 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-asp84ala (accessed [today's date]).

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