Is ADA2 p.Tyr353fs (c.1058_1061del) pathogenic?

ADA2 p.Tyr353fs (c.10581061del) is classified Pathogenic/Likely pathogenic in ADA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-01). Very rare (popmax 0.0011%, sas); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Tyr353fs (c.1058_1061del)?

ADA2 p.Tyr353fs (c.1058_1061del) is associated with deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Tyr353fs (c.1058_1061del) in the general population?

ADA2 p.Tyr353fs (c.1058_1061del) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Deficiency of adenosine deaminase 2 inherited?

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

ADA2 p.Tyr353fs

c.1058_1061del · rs2517294181 · VCV1954694

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.029	GERP -2, phastCons 0.69

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,082 alleles

Overall 6.84e-05% 1/1,461,474 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.Tyr353fs
Coding: c.1058_1061del
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs2517294181
Type: Deletion
Location: chr22:17188359 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 353: 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.Tyr353Asn Uncertain significance ★ same residue
ADA2 p.Ala221fs Pathogenic/Likely pathogenic ★★ same condition
ADA2 p.Asn53fs Pathogenic ★★ same condition
ADA2 p.His434_Pro435insTer Pathogenic ★★ same condition
ADA2 p.Lys314fs Pathogenic/Likely pathogenic ★★ same condition
ADA2 p.Lys466fs Pathogenic/Likely pathogenic ★★ same condition
ADA2 c.754-12del Likely benign ★★ same condition
ADA2 c.882-11del Benign/Likely benign ★★ 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-tyr353fs (accessed [today's date]).

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