Is CDKN2A p.Pro17Ser (c.49C>T) pathogenic?

CDKN2A p.Pro17Ser (c.49C>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-15). Ultra-rare (popmax 0.0121%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Pro17Ser (c.49C>T)?

CDKN2A p.Pro17Ser (c.49C>T) is associated with hereditary neoplastic syndrome, melanoma and neural system tumor syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Pro17Ser (c.49C>T) in the general population?

CDKN2A p.Pro17Ser (c.49C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

CDKN2A p.Pro17Ser

c.49C>T · rs3731190 · VCV655440

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.579	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.63, phastCons 1
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/90,860 alleles

Filtering AF 0.00678% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00523%

Overall 0.000811% 13/1,603,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,260
African / African-American	0.00134%	74,730
European (non-Finnish)	8.5e-05%	1,175,955

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.Pro17Ser
Coding: c.49C>T
MANE Select: NM_000077 · reported on NM_058195
dbSNP: rs3731190
Type: single nucleotide variant
Location: chr9:21994283 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 17: an α-helix; the 'interaction with cdk5rap3 and mdm2' region; a UniProt-annotated variant site (in)

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 familial melanoma

Similar variants

CDKN2A p.Ala17Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala17= Benign/Likely benign ★★ same residue
CDKN2A p.Pro17= Benign/Likely benign ★★ same residue
CDKN2A p.Ala17Asp Uncertain significance ★ ⚠ same residue
CDKN2A p.Ala17Phe Uncertain significance ★ same residue
CDKN2A p.Ala17Gly Uncertain significance ★ ⚠ 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-pro17ser (accessed [today's date]).

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