Is ADA2 p.Arg9Trp (c.25C>T) pathogenic?

ADA2 p.Arg9Trp (c.25C>T) is classified Conflicting classifications of pathogenicity in ADA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.0911); Very rare (popmax 0.00669%, eas); Associated with Sneddon syndrome.

What condition is associated with ADA2 p.Arg9Trp (c.25C>T)?

ADA2 p.Arg9Trp (c.25C>T) is associated with Sneddon syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Arg9Trp (c.25C>T) in the general population?

ADA2 p.Arg9Trp (c.25C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

How is Sneddon syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ADA2 p.Arg9Trp (c.25C>T)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

ADA2 p.Arg9Trp

c.25C>T · rs753994372 · VCV1442516

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Sneddon syndrome

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -3.5
Overall
CADD	0.431	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 0.00669% East Asian · 3/44,870 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00105% 17/1,612,712 alleles · very rare exomes 16/1,460,564 · genomes 1/152,148 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00788%	12,693
East Asiangrpmax	0.00669%	14,957
South Asian	0.00329%	30,351
Remaining individualsnot grpmax-eligible	0.0016%	62,444
European (non-Finnish)	0.000424%	235,919

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg9Trp
Coding: c.25C>T
MANE Select: NM_001282225
dbSNP: rs753994372
Type: single nucleotide variant
Location: chr22:17209653 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

Full ADA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Sneddon syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: deficiency of adenosine deaminase 2

For Sneddon syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ADA2 p.Arg9Gln Uncertain significance ★★ ⚠ same residue
ADA2 p.Arg9= Likely benign ★ same residue
TADA2A p.Asn9Ser 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

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-arg9trp (accessed [today's date]).

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