Is ADA2 p.Arg45Gly (c.133C>G) pathogenic?

ADA2 p.Arg45Gly (c.133C>G) is classified Uncertain significance in ADA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-28). AlphaMissense: likely benign (0.1221); Very rare (popmax 0.000169%, nfe); Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Arg45Gly (c.133C>G)?

ADA2 p.Arg45Gly (c.133C>G) is associated with autoinflammatory syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Arg45Gly (c.133C>G) in the general population?

ADA2 p.Arg45Gly (c.133C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ADA2 p.Arg45Gly (c.133C>G)?

AlphaMissense predicts likely benign (score 0.1221) — an in-silico prediction, not a clinical call.

ADA2 p.Arg45Gly

c.133C>G · rs777683953 · VCV844955

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.1221	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -8.13	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 1.1	GERP 0.73, phastCons 0.001
Overall
CADD	18.47	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,018 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,882 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: ADA2
Protein: p.Arg45Gly
Coding: c.133C>G
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs777683953
Type: single nucleotide variant
Location: chr22:17209545 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 45: a binding site

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

Also linked: deficiency of adenosine deaminase 2

Similar variants

ADA2 p.Arg45Gln Uncertain significance ★★ ⚠ same residue
ADA2 p.Arg45Trp Uncertain significance ★★ ⚠ same residue
ADA2 c.754-2A>G Likely pathogenic ★★ same condition
ADA2 c.882-2A>G Pathogenic ★★ same condition
ADA2 c.973-2A>G Pathogenic ★★ same condition
ADA2 p.Arg169Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ADA2 p.Arg169Trp Pathogenic/Likely pathogenic ★★ same condition
ADA2 p.Arg306Ter Likely 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/ada2-p-arg45gly (accessed [today's date]).

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