Is ADA2 p.Ile367Val (c.1099A>G) pathogenic?

ADA2 p.Ile367Val (c.1099A>G) is classified Uncertain significance in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-27). AlphaMissense: likely benign (0.0571); Very rare (popmax 0.00133%, afr); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Ile367Val (c.1099A>G)?

ADA2 p.Ile367Val (c.1099A>G) is associated with deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Ile367Val (c.1099A>G) in the general population?

ADA2 p.Ile367Val (c.1099A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Deficiency of adenosine deaminase 2 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ADA2 p.Ile367Val (c.1099A>G)?

AlphaMissense predicts likely benign (score 0.0571) — an in-silico prediction, not a clinical call.

ADA2 p.Ile367Val

c.1099A>G · rs780583418 · VCV1907183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
AlphaMissense	0.0571	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -3.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.3	GERP -3.2
Overall
CADD	0.036	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 0.00133% African / African-American · 1/75,046 alleles

Overall 6.2e-05% 1/1,613,720 alleles · very rare exomes 1/1,461,422 · genomes 0/152,298 · joint denominator

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.Ile367Val
Coding: c.1099A>G
MANE Select: NM_001282225
dbSNP: rs780583418
Type: single nucleotide variant
Location: chr22:17182744 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 367: the swirm domain; the 'disordered' region

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

Disease context

deficiency of adenosine deaminase 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Deficiency of adenosine deaminase 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

ADA2 p.Ile367Leu Uncertain significance ★★ ⚠ same residue
ADA2 p.Ile367Thr 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-ile367val (accessed [today's date]).

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