Is ADA2 p.Ile116Thr (c.347T>C) pathogenic?

ADA2 p.Ile116Thr (c.347T>C) is classified Uncertain significance in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-18). AlphaMissense: likely benign (0.0727); Very rare (popmax 8.5e-05%, nfe); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Ile116Thr (c.347T>C)?

ADA2 p.Ile116Thr (c.347T>C) is associated with deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Ile116Thr (c.347T>C) in the general population?

ADA2 p.Ile116Thr (c.347T>C) is very rare (popmax 8.5e-05%, nfe) (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.Ile116Thr (c.347T>C)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

ADA2 p.Ile116Thr

c.347T>C · rs2123709522 · VCV1400386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR 0.26	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 3.1	GERP -0.64, phastCons 0.99
Overall
CADD	12.48	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 8.5e-05% European (non-Finnish) · 1/1,176,092 alleles

Overall 6.86e-05% 1/1,456,906 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.Ile116Thr
Coding: c.347T>C
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs2123709522
Type: single nucleotide variant
Location: chr22:17207266 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 116: the sant domain; an α-helix

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 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-ile116thr (accessed [today's date]).

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