Is ADA2 p.Gly48Glu (c.143G>A) pathogenic?

ADA2 p.Gly48Glu (c.143G>A) is classified Uncertain significance in ADA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-22). AlphaMissense: ambiguous (0.371); Ultra-rare (popmax 0.0507%, afr); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Gly48Glu (c.143G>A)?

ADA2 p.Gly48Glu (c.143G>A) is associated with deficiency of adenosine deaminase 2, Sneddon syndrome, autoinflammatory syndrome (ClinVar).

How common is ADA2 p.Gly48Glu (c.143G>A) in the general population?

ADA2 p.Gly48Glu (c.143G>A) is ultra-rare (popmax 0.0507%, afr) (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.Gly48Glu (c.143G>A)?

AlphaMissense predicts ambiguous (score 0.371) — an in-silico prediction, not a clinical call.

ADA2 p.Gly48Glu

c.143G>A · rs140149634 · VCV541733

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.371 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0507%, afr)

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
AlphaMissense	0.371	ambiguous
REVEL	0.351	indeterminate
SaProt	LLR -11.23	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 0.66, phastCons 0.008
Overall
CADD	15.64	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 0.0507% African / African-American · 38/74,902 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0335%

Overall 0.00335% 54/1,613,418 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0507%	1,971
Middle Eastern	0.0165%	6,074
Remaining individualsnot grpmax-eligible	0.0032%	31,237
European (non-Finnish)	0.0011%	90,733

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.Gly48Glu
Coding: c.143G>A
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs140149634
Type: single nucleotide variant
Location: chr22:17209535 (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 autoinflammatory syndrome

For Deficiency of adenosine deaminase 2 (Orphanet):

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

Similar variants

ADA2 p.Gly48Ala Uncertain significance ★★ ⚠ same residue
ADA2 p.Gly48Val Uncertain significance ★★ ⚠ same residue
ADA2 p.Gly48Trp Likely pathogenic ★ same residue
ADA2 p.Gly48= 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

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-gly48glu (accessed [today's date]).

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