Is ADA p.Arg142Gln (c.425G>A) pathogenic?

ADA p.Arg142Gln (c.425G>A) is classified Benign in ADA (ClinVar, Expert panel, 16 submitters; last evaluated 2024-01-10). AlphaMissense: likely benign (0.0938); Low-frequency (popmax 1.31%, 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.Arg142Gln (c.425G>A) in the general population?

ADA p.Arg142Gln (c.425G>A) is low-frequency (popmax 1.31%, afr) (gnomAD).

What do computational predictors say about ADA p.Arg142Gln (c.425G>A)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

ADA p.Arg142Gln

Q: What condition is associated with ADA p.Arg142Gln (c.425G>A)?

ADA p.Arg142Gln (c.425G>A) 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.425G>A · rs61732239 · VCV68262

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.31%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

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

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

BS2_Supporting BA1

Curation rationale (ClinGen, verbatim)

NM_000022.4(ADA):c.425G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 142 (p.Arg142Gln). The filtering allele frequency (the upper threshold of the 95% CI of 975/74574 alleles) of the c.425G>A variant in ADA is 0.01222 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 and therefore meets this criterion (BA1). This variant has been observed in 6 homozygous individuals in gnomAD v.4, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1).

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

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -9.60	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 0.34	GERP -2.4
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	19.05	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 1.31% African / African-American · 975/74,574 alleles

Filtering AF 1.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.21%

Overall 0.0745% 1,181/1,585,270 alleles · low-frequency exomes 617/1,432,964 · genomes 564/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.31%	76
Remaining individualsnot grpmax-eligible	0.0994%	1,006
Admixed American	0.0871%	1,149
Middle Eastern	0.0554%	1,805
European (non-Finnish)	0.00764%	13,095
East Asian	0.00458%	21,820
South Asian	0.0023%	43,448

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.Arg142Gln
Coding: c.425G>A
MANE Select: NM_000022
dbSNP: rs61732239
Type: single nucleotide variant
Location: chr20:44625622 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 142: the 'required for binding to ddp4' region; a UniProt-annotated variant site (in); 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

ADA p.Arg142Ter Pathogenic ★★ same residue
ADA p.Arg142= Likely benign ★ 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-arg142gln (accessed [today's date]).

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