Is ADA2 p.Arg34Trp (c.100C>T) pathogenic?

ADA2 p.Arg34Trp (c.100C>T) is classified Conflicting classifications of pathogenicity in ADA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-15). AlphaMissense: likely benign (0.2338); Ultra-rare (popmax 0.0384%, amr); Associated with Sneddon syndrome.

What condition is associated with ADA2 p.Arg34Trp (c.100C>T)?

ADA2 p.Arg34Trp (c.100C>T) is associated with Sneddon syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Arg34Trp (c.100C>T) in the general population?

ADA2 p.Arg34Trp (c.100C>T) is ultra-rare (popmax 0.0384%, amr) (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.Arg34Trp (c.100C>T)?

AlphaMissense predicts likely benign (score 0.2338) — an in-silico prediction, not a clinical call.

ADA2 p.Arg34Trp

c.100C>T · rs750955849 · VCV570286

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2338 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Sneddon syndrome

Computational evidence

Protein change
AlphaMissense	0.2338	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -11.71	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.62	GERP 0.4
Overall
CADD	20.6	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 0.0384% Admixed American · 23/59,968 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00403% 65/1,613,954 alleles · ultra-rare exomes 62/1,461,858 · genomes 3/152,096 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0384%	2,607
European (non-Finnish)	0.0033%	30,257
South Asian	0.00329%	30,359

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.Arg34Trp
Coding: c.100C>T
MANE Select: NM_001282225
dbSNP: rs750955849
Type: single nucleotide variant
Location: chr22:17209578 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB
Residue 34: a binding site

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.Arg34Gln Uncertain significance ★ ⚠ same residue
ADA2 p.Arg34Pro Uncertain significance ★ ⚠ same residue
ADA2 p.Arg34= 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

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-arg34trp (accessed [today's date]).

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