Is ADA2 p.Met309Ile (c.927G>A) pathogenic?

ADA2 p.Met309Ile (c.927G>A) is classified Conflicting classifications of pathogenicity in ADA2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-03-01). AlphaMissense: ambiguous (0.3794); Low-frequency (popmax 1.19%, mid); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Met309Ile (c.927G>A)?

ADA2 p.Met309Ile (c.927G>A) is associated with deficiency of adenosine deaminase 2, Behcet disease, autoinflammatory syndrome (ClinVar).

How common is ADA2 p.Met309Ile (c.927G>A) in the general population?

ADA2 p.Met309Ile (c.927G>A) is low-frequency (popmax 1.19%, mid) (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.Met309Ile (c.927G>A)?

AlphaMissense predicts ambiguous (score 0.3794) — an in-silico prediction, not a clinical call.

ADA2 p.Met309Ile

c.927G>A · rs146597836 · VCV375247

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

ambiguous

0.3794 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.19%, mid)

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
AlphaMissense	0.3794	ambiguous
REVEL	0.291	indeterminate
SaProt	LLR -4.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP 0.25, phastCons 0.048
Overall
CADD	9.492	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 1.19% Middle Eastern · 72/6,060 alleles

Filtering AF 0.968% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.887%

Overall 0.155% 2,497/1,614,082 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.59%	18
Middle Easterngrpmax	1.19%	84
Ashkenazi Jewishnot grpmax-eligible	0.513%	195
Remaining individualsnot grpmax-eligible	0.227%	440
South Asian	0.209%	479
Admixed American	0.153%	652
European (non-Finnish)	0.151%	664
African / African-American	0.024%	4,170
Finnishnot grpmax-eligible	0.00625%	16,010

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.Met309Ile
Coding: c.927G>A
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs146597836
Type: single nucleotide variant
Location: chr22:17189987 (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: Behcet disease 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.Met309Thr 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-met309ile (accessed [today's date]).

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