Is ADA2 p.Cys159Tyr (c.476G>A) pathogenic?

ADA2 p.Cys159Tyr (c.476G>A) is classified Uncertain significance in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: ambiguous (0.5403); Very rare (popmax 0.000254%, nfe); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Cys159Tyr (c.476G>A)?

ADA2 p.Cys159Tyr (c.476G>A) is associated with deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Cys159Tyr (c.476G>A) in the general population?

ADA2 p.Cys159Tyr (c.476G>A) is very rare (popmax 0.000254%, 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.Cys159Tyr (c.476G>A)?

AlphaMissense predicts ambiguous (score 0.5403) — an in-silico prediction, not a clinical call.

ADA2 p.Cys159Tyr

c.476G>A · rs774636844 · VCV1496714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5403 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
AlphaMissense	0.5403	ambiguous
REVEL	0.704	pathogenic-leaning
SaProt	LLR -13.60	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.5, phastCons 1
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,042 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,886 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.Cys159Tyr
Coding: c.476G>A
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs774636844
Type: single nucleotide variant
Location: chr22:17207137 (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

TADA2A p.Ser159Ala 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
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-cys159tyr (accessed [today's date]).

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