Is CDKN2A p.Ala40Thr (c.118G>A) pathogenic?

CDKN2A p.Ala40Thr (c.118G>A) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). AlphaMissense: likely benign (0.1094); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala40Thr (c.118G>A)?

CDKN2A p.Ala40Thr (c.118G>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Ala40Thr (c.118G>A) in the general population?

CDKN2A p.Ala40Thr (c.118G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Ala40Thr (c.118G>A)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala40Thr

c.118G>A · VCV4224786

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -4.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1.2, phastCons 0.001
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN2A
Protein: p.Ala40Thr
Coding: c.118G>A
MANE Select: NM_000077
Type: single nucleotide variant
Location: chr9:21974710 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 40: 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.Ala40Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala40Val Uncertain significance ★ ⚠ same residue
CDKN2A p.Pro40= Likely benign ★ same residue
CDKN2A p.Pro40_Ala41delinsThr Uncertain significance ★ same residue
CDKN2A p.Ala40= Benign/Likely benign ★★ same residue
CDKN2A p.Ala40Pro Uncertain significance ★ ⚠ 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-ala40thr (accessed [today's date]).

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