Is ADA2 p.Met1Thr (c.2T>C) pathogenic?

ADA2 p.Met1Thr (c.2T>C) is classified Pathogenic in ADA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-26). Very rare (popmax 0.00467%, nfe); Associated with deficiency of adenosine deaminase 2.

What condition is associated with ADA2 p.Met1Thr (c.2T>C)?

ADA2 p.Met1Thr (c.2T>C) is associated with deficiency of adenosine deaminase 2 (ClinVar).

How common is ADA2 p.Met1Thr (c.2T>C) in the general population?

ADA2 p.Met1Thr (c.2T>C) is very rare (popmax 0.00467%, nfe) (gnomAD).

How is Deficiency of adenosine deaminase 2 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ADA2 p.Met1Thr

c.2T>C · rs745795188 · VCV1407177

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00467%, nfe)

Conditions

deficiency of adenosine deaminase 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.231	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.7, phastCons 0.86
Overall
CADD	11.73	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00467% European (non-Finnish) · 55/1,178,610 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00348% 56/1,610,314 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00467%	21,429
Remaining individualsnot grpmax-eligible	0.0016%	62,360

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.Met1Thr
Coding: c.2T>C
MANE Select: NM_001166105 · reported on NM_001282225
dbSNP: rs745795188
Type: single nucleotide variant
Location: chr22:17209676 (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

For Deficiency of adenosine deaminase 2 (Orphanet):

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

Similar variants

ADA2 p.Met1Lys Pathogenic ★ same residue
ADA2 p.Met1Ile Conflicting classifications of pathogenicity ★ 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

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-met1thr (accessed [today's date]).

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