Is ADA2 p.Thr65Met (c.194C>T) pathogenic?

ADA2 p.Thr65Met (c.194C>T) is classified Conflicting classifications of pathogenicity in ADA2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.078); Ultra-rare (popmax 0.0164%, mid); Associated with autoinflammatory syndrome.

What condition is associated with ADA2 p.Thr65Met (c.194C>T)?

ADA2 p.Thr65Met (c.194C>T) is associated with autoinflammatory syndrome, Sneddon syndrome, deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Thr65Met (c.194C>T) in the general population?

ADA2 p.Thr65Met (c.194C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ADA2 p.Thr65Met (c.194C>T)?

AlphaMissense predicts likely benign (score 0.078) — an in-silico prediction, not a clinical call.

ADA2 p.Thr65Met

c.194C>T · rs61747288 · VCV582996

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.078 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.078	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -7.82	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 0.15	GERP -1.5
Overall
CADD	7.957	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0126%

Overall 0.0411% 663/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.41%	71
Remaining individualsnot grpmax-eligible	0.0864%	1,157
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.0152%	6,592
South Asian	0.00549%	18,217
Admixed American	0.005%	19,989
East Asian	0.00445%	22,449
African / African-American	0.00134%	74,866

Ashkenazi Jewish 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.Thr65Met
Coding: c.194C>T
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs61747288
Type: single nucleotide variant
Location: chr22:17209484 (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: Sneddon syndrome deficiency of adenosine deaminase 2

Similar variants

ADA2 p.Thr65= 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
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-thr65met (accessed [today's date]).

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