Is ADA2 p.Arg169Trp (c.505C>T) pathogenic?

ADA2 p.Arg169Trp (c.505C>T) is classified Pathogenic/Likely pathogenic in ADA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-14). AlphaMissense: likely pathogenic (0.6246); Very rare (popmax 0.00167%, amr); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Arg169Trp (c.505C>T)?

ADA2 p.Arg169Trp (c.505C>T) is associated with deficiency of adenosine deaminase 2, Sneddon syndrome (ClinVar).

How common is ADA2 p.Arg169Trp (c.505C>T) in the general population?

ADA2 p.Arg169Trp (c.505C>T) 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.

What do computational predictors say about ADA2 p.Arg169Trp (c.505C>T)?

AlphaMissense predicts likely pathogenic (score 0.6246) — an in-silico prediction, not a clinical call.

ADA2 p.Arg169Trp

c.505C>T · rs775997344 · VCV956376

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
AlphaMissense	0.6246	likely pathogenic ✓ concordant with ClinVar
REVEL	0.583	indeterminate
SaProt	LLR -14.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.77	GERP -1.1, phastCons 0.003
Overall
CADD	20.1	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 0.00167% Admixed American · 1/60,020 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,864 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	0.000339%	295,004

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.Arg169Trp
Coding: c.505C>T
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs775997344
Type: single nucleotide variant
Location: chr22:17207108 (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

Also linked: Sneddon syndrome

For Deficiency of adenosine deaminase 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

ADA2 p.Arg169Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
TADA2A p.Met169Val 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.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-arg169trp (accessed [today's date]).

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