Is ADA2 p.Thr428Ile (c.1283C>T) pathogenic?

ADA2 p.Thr428Ile (c.1283C>T) is classified Uncertain significance in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-18). AlphaMissense: likely benign (0.0957); Absent from gnomAD v4.1; Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Thr428Ile (c.1283C>T)?

ADA2 p.Thr428Ile (c.1283C>T) is associated with autoinflammatory syndrome (ClinVar).

How common is ADA2 p.Thr428Ile (c.1283C>T) in the general population?

ADA2 p.Thr428Ile (c.1283C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADA2 p.Thr428Ile (c.1283C>T)?

AlphaMissense predicts likely benign (score 0.0957) — an in-silico prediction, not a clinical call.

ADA2 p.Thr428Ile

c.1283C>T · rs2123601456 · VCV1694256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0957 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0957	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -5.95	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 4.1	GERP 0.25, phastCons 0.34
Overall
CADD	11.6	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: ADA2
Protein: p.Thr428Ile
Coding: c.1283C>T
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs2123601456
Type: single nucleotide variant
Location: chr22:17181979 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 428: the swirm domain; a DNA-binding region

Full ADA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADA2 p.Arg169Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ADA2 p.Gly47Arg Pathogenic ★★ same condition
ADA2 p.His112Gln Pathogenic/Likely pathogenic ★★ same condition
ADA2 p.Tyr453Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ADA2 p.Ala27Ser Uncertain significance ★★ ⚠ same condition
ADA2 p.Ala345Pro Uncertain significance ★★ ⚠ same condition
ADA2 p.Ala35Val Uncertain significance ★★ ⚠ same condition
ADA2 p.Arg154Cys Uncertain significance ★★ ⚠ 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/ada2-p-thr428ile (accessed [today's date]).

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