# NM_000022.4(ADA):c.301C>T (p.Arg101Trp)

https://sugi.bio/variant/ada-p-arg101trp

## Summary

**ADA p.Arg101Trp (c.301C>T)** is classified **Pathogenic/Likely pathogenic** in ADA (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-09-16). AlphaMissense: likely pathogenic (0.8145); Very rare (popmax 0.00331%, nfe); Associated with ADA-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121908717 · 8 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00331%, nfe)

## For patients & families {#patients}

This is a change in the ADA gene that is considered likely disease-causing, submitted by 8 submitters, and is linked to ADA-related disorder.

*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.*

**Support & next steps:** [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.Arg101Trp |
| Coding change (HGVS c.) | c.301C>T |
| MANE Select transcript | [NM_000022](https://www.ncbi.nlm.nih.gov/nuccore/NM_000022) |
| dbSNP | [rs121908717](https://www.ncbi.nlm.nih.gov/snp/rs121908717/) |
| Variant type | single nucleotide variant |
| Location | chr20:44626517-44626517 (GRCh38) |
| ClinVar | [VCV1955](https://www.ncbi.nlm.nih.gov/clinvar/variation/1955/) |

**All HGVS expressions:** `LRG_16:g.30219C>T`, `LRG_16t1:c.301C>T`, `NC_000020.10:g.43255158G>A`, `NC_000020.11:g.44626517G>A`, `NG_007385.1:g.30219C>T`, `NM_000022.3:c.301C>T`, `NM_000022.4:c.301C>T`, `NM_001322050.2:c.12C>T`, `NM_001322051.2:c.301C>T`, `NR_136160.2:n.393C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8145) — concordant with the pathogenic call
- REVEL 0.939 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.539 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.197, GERP 1.39, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.41 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00331%** (nfe) · FAF95 0.00247% · FAF99 0.00217% · 39/1,180,024 in the highest group · 41/1,614,008 alleles overall — very rare (popmax 0.00331%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00331% | 30,257 |
| South Asian | 0.0022% | 45,540 |

*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 **101** lies in a UniProt-annotated variant site (in adascid); a UniProt-annotated variant site (in adascid; loss of activity); 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-16.

**Submitter consensus:** conflicting (4 Likely pathogenic, 2 Pathogenic, 1 not provided, 1 Uncertain significance).

**Submission history:** 8 submissions (1990–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-07-27 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1990-08-01 |
| UniProtKB/Swiss-Prot | not provided | no classification provided | not provided |  |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-04-25 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-17 |
| Genome-Nilou Lab | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-08-10 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-04-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-16 |

## Associated conditions {#conditions}

[ADA-related disorder](https://sugi.bio/atlas/disease/ada-related-disorder/), [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):** ADA-related disorder, Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, ADA-related condition, ADA-SCID, SCID DUE TO ADA DEFICIENCY, SCID DUE TO ADA DEFICIENCY, EARLY-ONSET, ADA deficiency, Severe combined immunodeficiency due to adenosine deaminase deficiency, Adenosine deaminase deficient severe combined immunodeficiency, Severe combined immunodeficiency due to ADA deficiency.

## Same-residue context {#hotspot}

Residue **101** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [ADA p.Arg101Gln](/variant/ada-p-arg101gln), [ADA p.Arg101Leu](/variant/ada-p-arg101leu), [ADA p.Arg101Gly](/variant/ada-p-arg101gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ADA variant pages (same residue, condition, or type): [ADA p.Arg101Gln](/variant/ada-p-arg101gln), [ADA p.Arg101Leu](/variant/ada-p-arg101leu), [ADA p.Arg101Gly](/variant/ada-p-arg101gly), [ADA p.Arg101=](/variant/ada-p-arg101), [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).

### 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 2026-07-14); 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 1955). 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.*