ADA p.Arg211His
c.632G>A · rs121908716 · VCV1957
ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP
Pathogenic for adenosine deaminase deficiency. Applied ACMG criteria (verbatim):
PP4_Moderate PP1_Strong PM2_Supporting PS3_Moderate PM3_Strong
Curation rationale (ClinGen, verbatim)
The NM_000022.4:c.632G>A variant in ADA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 211 (p.Arg211His). The filtering allele frequency (the upper threshold of the 95% CI of 10/35432) of the c.632G>A variant in ADA is 0.0001565 for Latino/Admixed American chromosomes by gnomAD v.2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). Total Expressed ADA Activity in SØ3834 in E. coli showed the values: Mean +- SD = 30.4 +- 35.8 (3.0–134.2)[nmol/h/mg protein] and the following percent of Wild Type (Range) = 0.012 - 0.014 (0.001–0.051), belonging to group I of Arredondo-Vega classification, indicating that this variant impacts protein function (PMID: 9758612, PS3_moderate). This variant has been detected in 22 individuals with SCID. Of those individuals, one was a heterozygous compound with c.95+1G>A (variant classified pathogenic according to the SCID VCEP specifications). The trans phase of the variants was confirmed by parental testing (1pt; PMID 9414266). Four individuals were with this variant, and a variant that has not been curated by the SCID VCEP (p.A179D, PMID 26684479; p.R101Q, PMID 16973956; p.Y201*, PMID 26255240, patient #46; p.L107P, PMID 19179314, patient #2) (0pt - These variants will not be curated now because the pathogenic level was already reached). Seventeen individuals were homozygous for the variant (maximum 1pt; PMID 27129325, 20460637, 26376800, 19179314, 16276484, 9758612). 2pts in total, PM3_Strong is met. At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome (0.5pt) + Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pt) + ADA-SCID phenotype corrected by ADA gene therapy (1pt), in a total of 4.5 points, which is highly specific for SCID (PP4_Moderate; PMID: 9414266). The variant has been reported to segregate with SCID in 4 affected family members from 2 families (LOD score 2.41; PP1_Strong; PMID 20460637, 26376800). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP4_Moderate, PM3_Strong, PP1_Strong, PM2_Supporting, PS3_Moderate. (VCEP specifications version 1).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.5475 | ambiguous |
|---|---|---|
| REVEL | 0.955 | strongly pathogenic-leaning |
| SaProt | LLR -14.54 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP -0.82, phastCons 1 |
| Regional constraint | o/e 0.94 | unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic |
| Overall | ||
| CADD | 33.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0217% | 4,616 |
| African / African-American | 0.016% | 6,244 |
| Remaining individualsnot grpmax-eligible | 0.0112% | 8,925 |
| East Asian | 0.00445% | 22,447 |
| South Asian | 0.00439% | 22,769 |
| European (non-Finnish) | 0.0028% | 35,757 |
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.Arg211His
- Coding
- c.632G>A
- MANE Select
- NM_000022
- dbSNP
- rs121908716
- Type
- single nucleotide variant
- Location
- chr20:44623053 (GRCh38)
- Gene constraint
- LOEUF 1.184 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 96.81 · 2 PDB
- Residue 211
- a UniProt-annotated variant site (in adascid; late onset; 4% of activity); a UniProt-annotated variant site (in adascid); a β-strand
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 & treatmentsFor 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.Arg211Cys Likely pathogenic ★★★ ⚠ same residue
- ADA p.Arg211Ser 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-arg211his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown