# NM_000022.4(ADA):c.307del (p.Ser103fs)

https://sugi.bio/variant/ada-p-ser103fs

## Summary

**ADA p.Ser103fs (c.307del)** is classified **Pathogenic** in ADA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-20). No gnomAD frequency available for this variant; Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2516175890 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ADA gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 19 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ADA is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Severe combined immunodeficiency due to adenosine deaminase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sinusitis — Frequent (79-30%)
- Recurrent otitis media — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)
- Lymphopenia — Frequent (79-30%)
- Diarrhea — Frequent (79-30%)
- Recurrent upper respiratory tract infections — Frequent (79-30%)
- Absence of lymph node germinal center — Frequent (79-30%)
- Autoimmunity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005748/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADA](https://sugi.bio/atlas/gene/ADA/) |
| Protein change (HGVS p.) | p.Ser103fs |
| Coding change (HGVS c.) | c.307del |
| MANE Select transcript | [NM_000022](https://www.ncbi.nlm.nih.gov/nuccore/NM_000022) |
| dbSNP | [rs2516175890](https://www.ncbi.nlm.nih.gov/snp/rs2516175890/) |
| Variant type | Deletion |
| Location | chr20:44626511-44626511 (GRCh38) |
| ClinVar | [VCV2034899](https://www.ncbi.nlm.nih.gov/clinvar/variation/2034899/) |

**All HGVS expressions:** `LRG_16:g.30225del`, `LRG_16t1:c.307del`, `NC_000020.10:g.43255152del`, `NC_000020.11:g.44626511del`, `NG_007385.1:g.30225del`, `NM_000022.4:c.307del`, `NM_001322050.2:c.18del`, `NM_001322051.2:c.307del`, `NR_136160.2:n.399del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.9, GERP 1.39, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.184, pLI 9.64e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ADA** population constraint: LOEUF 1.184, pLI 9.64e-15, missense-Z 0.4697. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.81, 97% of residues very-high.

**2 experimental structure(s)** (PDB): [3IAR](https://www.rcsb.org/structure/3IAR), [7RTG](https://www.rcsb.org/structure/7RTG).

## What this gene does {#gene-function}

*Describes the biological roles of ADA (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ADA's established molecular role includes adenosine deaminase activity. In Reactome, ADA is annotated in disease pathway(s) including **Defective ADA disrupts (deoxy)adenosine deamination**.

**Disease mechanism (Reactome):** ADA loss or alteration is curated in [Defective ADA disrupts (deoxy)adenosine deamination](https://reactome.org/content/detail/R-HSA-9734735).

### Pathways affected {#pathways}

ADA participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ADA disrupts (deoxy)adenosine deamination](https://reactome.org/content/detail/R-HSA-9734735) | curated |
| [Purine salvage](https://reactome.org/content/detail/R-HSA-74217) | curated |
| [Ribavirin ADME](https://reactome.org/content/detail/R-HSA-9755088) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** adenosine deaminase activity, zinc ion binding, deaminase activity, 2'-deoxyadenosine deaminase activity.

**Biological process:** response to hypoxia, adenosine catabolic process, response to purine-containing compound, purine nucleotide salvage, regulation of cell-cell adhesion mediated by integrin, T cell activation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-20.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-20 |

## Associated conditions {#conditions}

[severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency](https://sugi.bio/atlas/disease/severe-combined-immunodeficiency-autosomal-recessive-t-cell-negative-b-cell-negative-nk-cell-negative-due-to-adenosine-deaminase-deficiency/).

**Reported phenotype names (ClinVar):** Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, SCID DUE TO ADA DEFICIENCY, SCID DUE TO ADA DEFICIENCY, EARLY-ONSET, Adenosine deaminase deficient severe combined immunodeficiency, Severe combined immunodeficiency due to ADA deficiency, Adenosine Deaminase Deficiency, Severe combined immunodeficiency due to adenosine deaminase deficiency, ADA deficiency, ADA-SCID.

## Similar variants {#similar}

Related ADA variant pages (same residue, condition, or type): [ADA p.Val177_Val178insTer](/variant/ada-p-val177-val178inster), [ADA c.976-1_979del](/variant/ada-c-976-minus-1-979del), [ADA p.Arg324fs](/variant/ada-p-arg324fs), [ADA p.Asp123fs](/variant/ada-p-asp123fs), [ADA p.Glu319fs](/variant/ada-p-glu319fs), [ADA p.Gly136fs](/variant/ada-p-gly136fs), [ADA p.Leu137fs](/variant/ada-p-leu137fs), [ADA p.Leu236fs](/variant/ada-p-leu236fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2034899). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*