Is ADA p.Gln199Arg (c.596A>G) pathogenic?

ADA p.Gln199Arg (c.596A>G) is classified Uncertain significance in ADA (ClinVar, Expert panel, 2 submitters; last evaluated 2024-06-10). AlphaMissense: likely benign (0.0804); Very rare (popmax 0.0011%, sas); 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.Gln199Arg (c.596A>G) in the general population?

ADA p.Gln199Arg (c.596A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ADA p.Gln199Arg (c.596A>G)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

ADA p.Gln199Arg

Q: What condition is associated with ADA p.Gln199Arg (c.596A>G)?

ADA p.Gln199Arg (c.596A>G) 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.596A>G · rs121908734 · VCV2050660

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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

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

PM2_Supporting

Curation rationale (ClinGen, verbatim)

NM_000022.4:c.596A>G is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 199 (p.Gln199Arg). The highest population minor allele frequency in gnomAD v4 is 0.00001440 (1/69426 alleles) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). There are no publications for this variant in the literature. Based on insufficient evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_supporting.

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

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -8.27	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 1.9	GERP -0.81, phastCons 0.13
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	14.59	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,718 alleles

Overall 6.85e-05% 1/1,460,016 alleles · very rare

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.Gln199Arg
Coding: c.596A>G
MANE Select: NM_000022
dbSNP: rs121908734
Type: single nucleotide variant
Location: chr20:44624212 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 199: a UniProt-annotated variant site (in adascid; delayed-onset); 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.Gln199His Uncertain significance ★ ⚠ 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
ADA p.Ala329Val 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-gln199arg (accessed [today's date]).

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