Is ADA p.Met1Arg (c.2T>G) pathogenic?

ADA p.Met1Arg (c.2T>G) is classified Uncertain significance in ADA (ClinVar, Expert panel, 2 submitters; last evaluated 2026-03-26). Absent from gnomAD v4.1; Associated with severe combined immunodeficiency.

How common is ADA p.Met1Arg (c.2T>G) in the general population?

ADA p.Met1Arg (c.2T>G) is absent from gnomAD v4.1 (gnomAD).

ADA p.Met1Arg

Q: What condition is associated with ADA p.Met1Arg (c.2T>G)?

ADA p.Met1Arg (c.2T>G) is associated with severe combined immunodeficiency, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (ClinVar).

c.2T>G · rs1600956379 · VCV2709658

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

severe combined immunodeficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Uncertain Significance for severe combined immunodeficiency. Applied ACMG criteria (verbatim):

PVS1_Moderate PM2_Supporting PS3_Moderate

Curation rationale (ClinGen, verbatim)

The NM_000022.4(ADA):c.2T>G is a missense variant predicted to cause substitution of Methionine by Arginine at amino acid 1 (p.Met1Arg). This sequence change affects the initiator methionine of the ADA mRNA. The next possible initiation codon is at codon 52. This variant is absent from gnomAD v4.1.0, good coverage (PM2_supporting). The NM_000022.4:c.2T>G variant in ADA may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Moderate). ADA enzyme activity assay in E. coli S3834 showed 0.01% of wild-type activity for the p.Met1Arg variant, indicating severely reduced protein function consistent with loss of function (PS3_Moderate). In summary, this variant meets the criteria to be classified as uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen ClinGen SCID-VCEP: PM2_supporting, PVS1_moderate, PS3_moderate. (VCEP specifications version 2.1.0).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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	0.622	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.2, phastCons 1
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADA
Protein: p.Met1Arg
Coding: c.2T>G
MANE Select: NM_000022
dbSNP: rs1600956379
Type: single nucleotide variant
Location: chr20:44651606 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB

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

Disease context

severe combined immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Similar variants

ADA p.Met1Thr Pathogenic/Likely pathogenic ★★ same residue
ADA p.Met1Val Pathogenic/Likely pathogenic ★★ same residue
ADA c.1078+2T>A Likely pathogenic ★★★ same condition
ADA c.219-2A>G Likely pathogenic ★★★ same condition
ADA c.363-2A>G Likely pathogenic ★★★ same condition
ADA c.606+1G>T Likely pathogenic ★★★ same condition
ADA c.975+1G>A Pathogenic ★★★ same condition
ADA c.976-1G>C 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/ada-p-met1arg (accessed [today's date]).

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