Is CDKN2A p.Pro37= (c.111A>G) pathogenic?

CDKN2A p.Pro37= (c.111A>G) is classified Benign/Likely benign in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-12). Ultra-rare (popmax 0.0197%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Pro37= (c.111A>G)?

CDKN2A p.Pro37= (c.111A>G) is associated with hereditary neoplastic syndrome, melanoma-pancreatic cancer syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Pro37= (c.111A>G) in the general population?

CDKN2A p.Pro37= (c.111A>G) is ultra-rare (popmax 0.0197%, mid) (gnomAD).

CDKN2A p.Pro37=

c.111A>G · rs1039977006 · VCV1086368

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, mid)

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 -0.19	GERP -3.1
Overall
CADD	10.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0197% Middle Eastern · 1/5,086 alleles

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

Overall 0.000276% 4/1,450,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0197%	5,086
Finnishnot grpmax-eligible	0.00178%	56,334
European (non-Finnish)	0.00017%	589,341

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.Pro37=
Coding: c.111A>G
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs1039977006
Type: single nucleotide variant
Location: chr9:21994221 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 37: 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.Leu37Arg Uncertain significance ★★ ⚠ same residue
CDKN2A p.Pro37Arg Uncertain significance ★★ same residue
CDKN2A p.Pro37Ala Uncertain significance ★ same residue
CDKN2A p.Pro37Leu Uncertain significance ★ same residue
CDKN2A p.Leu37= Likely benign ★ same residue
CDKN2A p.Leu37Pro Likely benign ★ same residue
CDKN2A p.Leu37_Pro38insLeuGluAlaGlyAlaLeu Uncertain significance ★ 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-pro37 (accessed [today's date]).

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