Is ADA2 p.Arg9Gln (c.26G>A) pathogenic?

ADA2 p.Arg9Gln (c.26G>A) is classified Uncertain significance in ADA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-07). AlphaMissense: likely benign (0.0929); Ultra-rare (popmax 0.0461%, sas); Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Arg9Gln (c.26G>A)?

ADA2 p.Arg9Gln (c.26G>A) is associated with autoinflammatory syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Arg9Gln (c.26G>A) in the general population?

ADA2 p.Arg9Gln (c.26G>A) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about ADA2 p.Arg9Gln (c.26G>A)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

ADA2 p.Arg9Gln

c.26G>A · rs766367978 · VCV649840

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -7.71	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 -6	GERP -3.5
Overall
CADD	0.279	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 0.0461% South Asian · 42/91,070 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00335% 54/1,613,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,168
Remaining individualsnot grpmax-eligible	0.008%	12,494
African / African-American	0.00134%	74,886
European (non-Finnish)	0.000509%	196,638

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.Arg9Gln
Coding: c.26G>A
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs766367978
Type: single nucleotide variant
Location: chr22:17209652 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

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.Arg9Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
ADA2 p.Arg9= Likely benign ★ same residue
TADA2A p.Asn9Ser 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

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-arg9gln (accessed [today's date]).

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