Is ADA2 p.Tyr220Ter (c.660C>G) pathogenic?

ADA2 p.Tyr220Ter (c.660C>G) is classified Pathogenic in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). Very rare (popmax 0.00167%, amr); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Tyr220Ter (c.660C>G)?

ADA2 p.Tyr220Ter (c.660C>G) is associated with deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Tyr220Ter (c.660C>G) in the general population?

ADA2 p.Tyr220Ter (c.660C>G) is very rare (popmax 0.00167%, amr) (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.Tyr220Ter

c.660C>G · rs2231487 · VCV2417153

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	Δ0.99	acceptor gain · deltas
Pangolin	Δ0.84	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -6.4	GERP -1.8
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,014 alleles

Overall 6.84e-05% 1/1,461,564 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.Tyr220Ter
Coding: c.660C>G
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs2231487
Type: single nucleotide variant
Location: chr22:17203656 (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.Tyr220= Benign/Likely benign ★★ 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
ADA2 p.Arg312Ter 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-tyr220ter (accessed [today's date]).

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