Is ADA2 p.Tyr453= (c.1359T>C) pathogenic?

ADA2 p.Tyr453= (c.1359T>C) is classified Benign/Likely benign in ADA2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 33.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Tyr453= (c.1359T>C)?

ADA2 p.Tyr453= (c.1359T>C) is associated with deficiency of adenosine deaminase 2 (ClinVar).

How is Deficiency of adenosine deaminase 2 inherited?

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

ADA2 p.Tyr453=

Q: How common is ADA2 p.Tyr453= (c.1359T>C) in the general population?

ADA2 p.Tyr453= (c.1359T>C) is common (popmax 33.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1359T>C · rs7289170 · VCV402527

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 33.9%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -2.3
Overall
CADD	0.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 33.9% European (non-Finnish) · 399,270/1,179,514 alleles

Filtering AF 33.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 33.7%

Overall 30.7% 494,735/1,613,476 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	33.9%	3
Finnishnot grpmax-eligible	32.2%	3
Middle Eastern	31.9%	3
Remaining individualsnot grpmax-eligible	29.3%	3
Ashkenazi Jewishnot grpmax-eligible	28.1%	4
African / African-American	23.6%	4
Amishnot grpmax-eligible	22.6%	4
Admixed American	17.3%	6
South Asian	17.2%	6
East Asian	5.16%	19

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.Tyr453=
Coding: c.1359T>C
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs7289170
Type: single nucleotide variant
Location: chr22:17181903 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

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.Tyr453Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
ADA2 p.Tyr453His 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-tyr453 (accessed [today's date]).

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