ADA p.Val133fs
c.396dup · rs1555844617 · VCV550821
ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP
Pathogenic for adenosine deaminase deficiency. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PP4_Met
Curation rationale (ClinGen, verbatim)
The c.396dup (p.Val133Serfs*38) (NM_000022.4) variant in ADA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pt) + T-B-NK- lymphocyte subset profile (0.5pt) = 1 point TOTAL, which is highly specific for SCID (PP4_Met, PMID: 21664875). 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: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1).
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 | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 5 of 12 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 4.8 | GERP 1.4, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
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.Val133fs
- Coding
- c.396dup
- MANE Select
- NM_000022
- dbSNP
- rs1555844617
- Type
- Duplication
- Location
- chr20:44625650 (GRCh38)
- Gene constraint
- LOEUF 1.184 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 96.81 · 2 PDB
- Residue 133
- the 'required for binding to ddp4' region; an α-helix
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 & treatmentsAlso linked: severe combined immunodeficiency
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.Val133= Likely benign ★ same residue
- ADA p.Asn285fs Pathogenic/Likely pathogenic ★★ same condition
- ADA p.Glu217fs Pathogenic ★★ same condition
- ADA p.Leu193fs Pathogenic/Likely pathogenic ★★ same condition
- ADA p.Leu231fs Pathogenic/Likely pathogenic ★★ same condition
- ADA p.Val178fs Pathogenic ★★ same condition
- ADA p.Asn293delinsThrGlyTer Pathogenic ★ same condition
- ADA p.Gln119fs 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-val133fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown