Is ADA2 p.Val349Ile (c.1045G>A) pathogenic?

ADA2 p.Val349Ile (c.1045G>A) is classified Benign/Likely benign in ADA2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0719); Rare (popmax 0.398%, nfe); Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Val349Ile (c.1045G>A)?

ADA2 p.Val349Ile (c.1045G>A) is associated with autoinflammatory syndrome, Behcet disease, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Val349Ile (c.1045G>A) in the general population?

ADA2 p.Val349Ile (c.1045G>A) is rare (popmax 0.398%, nfe) (gnomAD).

What do computational predictors say about ADA2 p.Val349Ile (c.1045G>A)?

AlphaMissense predicts likely benign (score 0.0719) — an in-silico prediction, not a clinical call.

ADA2 p.Val349Ile

c.1045G>A · rs74317375 · VCV430693

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.398%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -6.22	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 -3.7	GERP -3
Overall
CADD	0.158	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 0.398% European (non-Finnish) · 4,693/1,179,958 alleles

Filtering AF 0.388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.384%

Overall 0.322% 5,197/1,614,100 alleles · rare exomes 4,858/1,461,762 · genomes 339/152,338 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.398%	251
Remaining individualsnot grpmax-eligible	0.366%	273
Admixed American	0.197%	509
Middle Eastern	0.115%	866
African / African-American	0.0773%	1,294
Finnishnot grpmax-eligible	0.0765%	1,307
South Asian	0.0428%	2,335
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868
East Asian	0.00223%	44,862

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.Val349Ile
Coding: c.1045G>A
MANE Select: NM_001282225
dbSNP: rs74317375
Type: single nucleotide variant
Location: chr22:17188375 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 349: the 'disordered' 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

Also linked: Behcet disease deficiency of adenosine deaminase 2

Similar variants

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
ADA2 p.Arg312Ter Pathogenic ★★ same condition
ADA2 p.Asn370Lys 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-val349ile (accessed [today's date]).

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