Is CDKN2A p.Arg46Gln (c.137G>A) pathogenic?

CDKN2A p.Arg46Gln (c.137G>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-06-09). AlphaMissense: ambiguous (0.5586); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Arg46Gln (c.137G>A)?

CDKN2A p.Arg46Gln (c.137G>A) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Arg46Gln (c.137G>A) in the general population?

CDKN2A p.Arg46Gln (c.137G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CDKN2A p.Arg46Gln (c.137G>A)?

AlphaMissense predicts ambiguous (score 0.5586) — an in-silico prediction, not a clinical call.

CDKN2A p.Arg46Gln

c.137G>A · rs1554656241 · VCV631208

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5586	ambiguous
REVEL	0.58	indeterminate
SaProt	LLR -7.30	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 2, phastCons 0.26
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	25.1	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 0.0011% South Asian · 1/91,084 alleles

Overall 6.2e-05% 1/1,614,006 alleles · very rare exomes 1/1,461,692 · genomes 0/152,314 · 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.Arg46Gln
Coding: c.137G>A
MANE Select: NM_000077
dbSNP: rs1554656241
Type: single nucleotide variant
Location: chr9:21974691 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 46: 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: familial melanoma

Similar variants

CDKN2A p.Arg46Trp Uncertain significance ★★ ⚠ same residue
CDKN2A p.Val46Met Uncertain significance ★★ same residue
CDKN2A p.Val46= Benign/Likely benign ★★ same residue
CDKN2A p.Arg46= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Arg46Pro Uncertain significance ★ ⚠ same residue
CDKN2A p.Val46Ala Uncertain significance ★ same residue
CDKN2A p.Val46Gly Uncertain significance ★ same residue
CDKN2A p.Val46Leu Uncertain significance ★ same residue

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-arg46gln (accessed [today's date]).

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