Is CDKN2A p.Ala19Thr (c.55G>A) pathogenic?

CDKN2A p.Ala19Thr (c.55G>A) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: likely pathogenic (0.6153); Very rare (popmax 6.88e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala19Thr (c.55G>A)?

CDKN2A p.Ala19Thr (c.55G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Ala19Thr (c.55G>A) in the general population?

CDKN2A p.Ala19Thr (c.55G>A) is very rare (popmax 6.88e-05%) (gnomAD).

What do computational predictors say about CDKN2A p.Ala19Thr (c.55G>A)?

AlphaMissense predicts likely pathogenic (score 0.6153) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala19Thr

c.55G>A · VCV4224776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6153 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.88e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6153	likely pathogenic
REVEL	0.58	indeterminate
SaProt	LLR -14.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.88e-05%

Overall 6.88e-05% 1/1,454,430 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.Ala19Thr
Coding: c.55G>A
MANE Select: NM_000077
Type: single nucleotide variant
Location: chr9:21974773 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 19: an α-helix; a UniProt-annotated variant site (in cmm2; loss of cdk4 binding); 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.Arg19Gln Uncertain significance ★★ same residue
CDKN2A p.Arg19Leu Uncertain significance ★★ same residue
CDKN2A p.Ala19= Benign/Likely benign ★★ same residue
CDKN2A p.Ala19Asp Uncertain significance ★ ⚠ same residue
CDKN2A p.Arg19Pro Uncertain significance ★ same residue
CDKN2A p.Ala19_Ala20insThrAla Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Arg19_Val20insTer Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Arg19Ter Likely pathogenic ★ 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-ala19thr (accessed [today's date]).

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