Is CDKN2A p.Asp116Tyr (c.346G>T) pathogenic?

CDKN2A p.Asp116Tyr (c.346G>T) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-21). AlphaMissense: ambiguous (0.5072); Very rare (popmax 6.87e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Asp116Tyr (c.346G>T)?

CDKN2A p.Asp116Tyr (c.346G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Asp116Tyr (c.346G>T) in the general population?

CDKN2A p.Asp116Tyr (c.346G>T) is very rare (popmax 6.87e-05%) (gnomAD).

What do computational predictors say about CDKN2A p.Asp116Tyr (c.346G>T)?

AlphaMissense predicts ambiguous (score 0.5072) — an in-silico prediction, not a clinical call.

CDKN2A p.Asp116Tyr

c.346G>T · rs1477500164 · VCV2563909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.87e-05%)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5072	ambiguous
REVEL	0.451	indeterminate
SaProt	LLR -14.14	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	26.5	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 6.87e-05%

Overall 6.87e-05% 1/1,455,880 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.Asp116Tyr
Coding: c.346G>T
MANE Select: NM_000077
dbSNP: rs1477500164
Type: single nucleotide variant
Location: chr9:21971013 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 116: an α-helix; a UniProt-annotated variant site (in); the 'disordered' 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.Asp116Glu Uncertain significance ★★ ⚠ same residue
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>C Pathogenic ★★ same condition
CDKN2A c.151-1G>T Pathogenic/Likely pathogenic ★★ same condition
CDKN2A c.151-2A>G Pathogenic/Likely pathogenic ★★ same condition
CDKN2A c.193+2T>C Likely pathogenic ★★ same condition
CDKN2A c.193+5G>A Pathogenic/Likely pathogenic ★★ same condition
CDKN2A c.194-3653G>T 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-asp116tyr (accessed [today's date]).

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