Is ADA2 p.Ile462= (c.1386T>C) pathogenic?

ADA2 p.Ile462= (c.1386T>C) is classified Conflicting classifications of pathogenicity in ADA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-14). Ultra-rare (popmax 0.0166%, mid); Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Ile462= (c.1386T>C)?

ADA2 p.Ile462= (c.1386T>C) is associated with autoinflammatory syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Ile462= (c.1386T>C) in the general population?

ADA2 p.Ile462= (c.1386T>C) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

ADA2 p.Ile462=

c.1386T>C · rs373797039 · VCV474906

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.9	GERP -2.3
Overall
CADD	1.236	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,024 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.0102% 165/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	6.47%	15
Middle Easterngrpmax	0.0166%	6,024
Admixed American	0.01%	10,004
European (non-Finnish)	0.00814%	12,292
Remaining individualsnot grpmax-eligible	0.0032%	31,252
African / African-American	0.00133%	75,050

Amish 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.Ile462=
Coding: c.1386T>C
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs373797039
Type: single nucleotide variant
Location: chr22:17181876 (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.Ile462Thr 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-ile462 (accessed [today's date]).

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