Is CDKN2A p.Arg22= (c.66G>A) pathogenic?

CDKN2A p.Arg22= (c.66G>A) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-08-13). Very rare (popmax 0.00017%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Arg22= (c.66G>A)?

CDKN2A p.Arg22= (c.66G>A) is associated with hereditary neoplastic syndrome, melanoma-pancreatic cancer syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Arg22= (c.66G>A) in the general population?

CDKN2A p.Arg22= (c.66G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

CDKN2A p.Arg22=

c.66G>A · rs776810546 · VCV230052

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

hereditary neoplastic syndrome

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 0.6	GERP 0.15, phastCons 0.12
Overall
CADD	13.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,410 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,457,326 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.Arg22=
Coding: c.66G>A
MANE Select: NM_000077
dbSNP: rs776810546
Type: single nucleotide variant
Location: chr9:21974762 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 22: the 'interaction with cdk5rap3 and mdm2' 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-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.Arg22Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg22Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg22Trp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg22Leu Uncertain significance ★ ⚠ same residue
CDKN2A p.Val22Ile Uncertain significance ★ same residue
CDKN2A p.Val22= Benign ★ same residue
CDKN2A p.Arg22fs Pathogenic ★ same residue
CDKN2A c.150+1G>A 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-arg22 (accessed [today's date]).

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