Is CDKN2A p.Thr18Pro (c.52A>C) pathogenic?

CDKN2A p.Thr18Pro (c.52A>C) is classified Likely pathogenic in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-03). AlphaMissense: likely benign (0.3192); Very rare (popmax 0.0022%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Thr18Pro (c.52A>C)?

CDKN2A p.Thr18Pro (c.52A>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Thr18Pro (c.52A>C) in the general population?

CDKN2A p.Thr18Pro (c.52A>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CDKN2A p.Thr18Pro (c.52A>C)?

AlphaMissense predicts likely benign (score 0.3192) — an in-silico prediction, not a clinical call.

CDKN2A p.Thr18Pro

c.52A>C · rs758455611 · VCV232702

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3192	likely benign ⚠ discordant with ClinVar
REVEL	0.229	benign-leaning
SaProt	LLR -13.23	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.1	GERP -4.1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	9.997	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 0.0022% South Asian · 2/90,950 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000138% 2/1,453,832 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.Thr18Pro
Coding: c.52A>C
MANE Select: NM_000077
dbSNP: rs758455611
Type: single nucleotide variant
Location: chr9:21974776 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 18: an α-helix; 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

Similar variants

CDKN2A p.Pro18Arg Uncertain significance ★★ same residue
CDKN2A p.Pro18Leu Uncertain significance ★★ same residue
CDKN2A p.Thr18Lys Uncertain significance ★★ ⚠ same residue
CDKN2A p.Pro18= Benign/Likely benign ★★ same residue
CDKN2A p.Thr18Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Thr18fs Pathogenic ★ same residue
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>C 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-thr18pro (accessed [today's date]).

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