Is ADA2 p.Gln145His (c.435G>C) pathogenic?

ADA2 p.Gln145His (c.435G>C) is classified Uncertain significance in ADA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-10). AlphaMissense: likely benign (0.1811); Very rare (popmax 0.00833%, amr); Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Gln145His (c.435G>C)?

ADA2 p.Gln145His (c.435G>C) is associated with autoinflammatory syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Gln145His (c.435G>C) in the general population?

ADA2 p.Gln145His (c.435G>C) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about ADA2 p.Gln145His (c.435G>C)?

AlphaMissense predicts likely benign (score 0.1811) — an in-silico prediction, not a clinical call.

ADA2 p.Gln145His

c.435G>C · rs752626692 · VCV1450888

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.1811	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -6.82	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 -0.28	GERP 0.46
Overall
CADD	12.51	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,006 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00539% 87/1,614,098 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,001
European (non-Finnish)	0.00686%	14,568
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Gln145His
Coding: c.435G>C
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs752626692
Type: single nucleotide variant
Location: chr22:17207178 (GRCh38)
Structure: AlphaFold pLDDT 85.04 · 1 PDB

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

Disease context

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

Also linked: deficiency of adenosine deaminase 2

Similar variants

ADA2 p.Gln145Pro 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-gln145his (accessed [today's date]).

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