Is CDKN2A p.Ala76Val (c.227C>T) pathogenic?

CDKN2A p.Ala76Val (c.227C>T) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). AlphaMissense: likely benign (0.1339); Absent from gnomAD v4.1.

How common is CDKN2A p.Ala76Val (c.227C>T) in the general population?

CDKN2A p.Ala76Val (c.227C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Ala76Val (c.227C>T)?

AlphaMissense predicts likely benign (score 0.1339) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala76Val

c.227C>T · VCV4532853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1339 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1339	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -5.92	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 -0.47	GERP -4.1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	10.89	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.Ala76Val
Coding: c.227C>T
MANE Select: NM_000077
Type: single nucleotide variant
Location: chr9:21971132 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 76: a turn; the 'disordered' region

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKN2A p.Ala76Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala76Gly Uncertain significance ★ same residue
CDKN2A p.Ala76Ser Uncertain significance ★ ⚠ same residue
CDKN2A p.Ala76fs Pathogenic/Likely pathogenic ★★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same type
CDKN2A c.150+2T>G Likely pathogenic ★★ same type
CDKN2A c.151-1G>A Pathogenic ★★ same type
CDKN2A c.151-1G>C Pathogenic ★★ same type

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-ala76val (accessed [today's date]).

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