# NM_000022.4(ADA):c.703C>T (p.Arg235Trp)

https://sugi.bio/variant/ada-p-arg235trp

## Summary

**ADA p.Arg235Trp (c.703C>T)** is classified **Likely pathogenic** in ADA (ClinVar, Expert panel, 6 submitters; last evaluated 2023-11-14). AlphaMissense: likely pathogenic (0.8648); Very rare (popmax 0.00223%, eas); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs778809577 · 6 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the ADA gene that is considered likely disease-causing, submitted by 6 submitters, 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.Arg235Trp |
| Coding change (HGVS c.) | c.703C>T |
| MANE Select transcript | [NM_000022](https://www.ncbi.nlm.nih.gov/nuccore/NM_000022) |
| dbSNP | [rs778809577](https://www.ncbi.nlm.nih.gov/snp/rs778809577/) |
| Variant type | single nucleotide variant |
| Location | chr20:44622906-44622906 (GRCh38) |
| ClinVar | [VCV468281](https://www.ncbi.nlm.nih.gov/clinvar/variation/468281/) |

**All HGVS expressions:** `LRG_16:g.33830C>T`, `LRG_16t1:c.703C>T`, `NC_000020.10:g.43251547G>A`, `NC_000020.11:g.44622906G>A`, `NG_007385.1:g.33830C>T`, `NM_000022.3:c.703C>T`, `NM_000022.4:c.703C>T`, `NM_001322050.2:c.298C>T`, `NM_001322051.2:c.631C>T`, `NR_136160.2:n.795C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8648) — concordant with the pathogenic call
- REVEL 0.97 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.789 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 0.779, GERP -0.526, phastCons 1 — weakly conserved position
- CADD: **PHRED 26.3**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.94** across the covering region of the MANE Select transcript (44,619,837–44,651,607), spanning 31,770 bp. Chi-square p 0.21. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000542% · FAF99 0.000428% · 1/44,900 in the highest group · 18/1,614,096 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| East Asian (grpmax) | 0.00223% | 44,900 |
| South Asian | 0.0022% | 45,546 |
| African / African-American | 0.00133% | 74,916 |
| European (non-Finnish) | 0.00102% | 98,338 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **235** lies in a β-strand.

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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2023-11-14.

**Submitter consensus:** conflicting (3 Likely pathogenic, 3 Pathogenic).

**Submission history:** 6 submissions (2018–2023); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Severe Combined Immunodeficiency Disease VCEP (adenosine deaminase deficiency). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PM5_Supporting`, `PM3_Strong`, `PP4_Met`.
*Considered but not met:* `PM6`, `PS1`, `PS2`, `PS3`, `PP1`, `BS3`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.703C>T (NM_000022.4) variant in ADA gene is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 235 (p.Arg235Trp). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/113770 observed alleles) is 0.000002920 in gnomAD v2.1.1 which is below than SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting).  This variant has been detected in at least 5 individuals with SCID. Of those individuals, 2 were compound heterozygous: Patient #6, W264X, reported by Dalal I et al. (PMID: 21624848, Pathogenic according to the SCID VCEP specifications, confirmed in trans, 1pt) and Patient #26, p.G74D, reported by Chi ZH et al. (PMID: 30290665, Likey Pathogenic according to the SCID VCEP, confirmed in trans, 1 pt). 3 individuals were homozygous for PMIDs: 26255240, 26376800, and 32307643; reaching the limit for homozygous occurrence = 1 pt). Total = 3 pts, PM3_Strong. Evaluating those 5 probands, three of them had PP4 applied at supporting level: * PMID: 30290665: 171 PID-related genes(NGS panel: 0.5pt); T-B-SCID ( SCID gene panel which ruled out alternative causes 0.5pt); SCID diagnostic (0.5pt); Total 1.5pts. * PMID: 26376800: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt. TOTAL: 1.5 pts, PP4_Met. * PMID: 26255240: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt = TOTAL: 1.5 pts = PP4_Met.  In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PP4, PM3_Strong, and PM5_supporting. (VCEP specifications version 1).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50091 · approved 2024-01-16 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/ff38cc3b-e966-4c99-ab3c-49f5c18a6446).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-08-10 |
| Natera, Inc. | Pathogenic | no assertion criteria provided | clinical testing | 2021-03-30 |
| ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Likely pathogenic | reviewed by expert panel | curation | 2023-11-14 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-27 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2018-04-12 |

## 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, ADA-related disorder, ADA-related condition, ADA-SCID, Severe combined immunodeficiency due to adenosine deaminase deficiency, SCID DUE TO ADA DEFICIENCY, SCID DUE TO ADA DEFICIENCY, EARLY-ONSET, ADA deficiency, Adenosine deaminase deficient severe combined immunodeficiency, Severe combined immunodeficiency due to ADA deficiency.

## Same-residue context {#hotspot}

Residue **235** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ADA p.Arg235Gln](/variant/ada-p-arg235gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ADA variant pages (same residue, condition, or type): [ADA p.Arg235Gln](/variant/ada-p-arg235gln), [ADA p.Arg235=](/variant/ada-p-arg235), [ADA c.1078+2T>A](/variant/ada-c-1078-plus-2t-a), [ADA c.219-2A>G](/variant/ada-c-219-minus-2a-g), [ADA c.363-2A>G](/variant/ada-c-363-minus-2a-g), [ADA c.606+1G>T](/variant/ada-c-606-plus-1g-t), [ADA c.975+1G>A](/variant/ada-c-975-plus-1g-a), [ADA c.976-1G>C](/variant/ada-c-976-minus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 468281). 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.*