Is ADA p.Gly134= (c.402C>T) pathogenic?

ADA p.Gly134= (c.402C>T) is classified Likely benign in ADA (ClinVar, Expert panel, 8 submitters; last evaluated 2023-11-14). Rare (popmax 0.457%, afr); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency.

How common is ADA p.Gly134= (c.402C>T) in the general population?

ADA p.Gly134= (c.402C>T) is rare (popmax 0.457%, afr) (gnomAD).

ADA p.Gly134=

Q: What condition is associated with ADA p.Gly134= (c.402C>T)?

ADA p.Gly134= (c.402C>T) is associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (ClinVar).

Q: How is Severe combined immunodeficiency due to adenosine deaminase deficiency inherited?

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

c.402C>T · rs146921882 · VCV536186

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.457%, afr)

Conditions

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

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Likely Benign for adenosine deaminase deficiency. Applied ACMG criteria (verbatim):

BS1 BS2_Supporting BP7

Curation rationale (ClinGen, verbatim)

The c.402C>T (p.Gly134=) variant (NM_000022.4) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.003095 (89/19874 alleles) in African/African American population, which is higher than the ClinGen SCID VCEP threshold (>0.00161) for BS1, and therefore meets this criterion (BS1). In the gnomAD v2.1.1 database, this variant has been observed in 1 homozygous individual with no features of SCID, a condition with full penetrance at an early age. BS2_supporting is met. In summary, this variant is classified as a Likely Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BS1, BP7, and BS2_Supporting.

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Overall
CADD	9.416	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.457% African / African-American · 340/74,348 alleles

Filtering AF 0.417% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.402%

Overall 0.0256% 403/1,575,650 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.457%	219
Admixed American	0.0677%	1,478
Remaining individualsnot grpmax-eligible	0.0393%	2,542
South Asian	0.00233%	42,986

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: ADA
Protein: p.Gly134=
Coding: c.402C>T
MANE Select: NM_000022
dbSNP: rs146921882
Type: single nucleotide variant
Location: chr20:44625645 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 134: the 'required for binding to ddp4' region; an α-helix

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

Disease context

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe combined immunodeficiency due to adenosine deaminase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

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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
ADA p.Ala329Val Pathogenic ★★★ same condition
ADA p.Arg149Trp 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/ada-p-gly134 (accessed [today's date]).

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