# NM_000022.4(ADA):c.446G>A (p.Arg149Gln)

https://sugi.bio/variant/ada-p-arg149gln

## Summary

**ADA p.Arg149Gln (c.446G>A)** is classified **Uncertain significance** in ADA (ClinVar, Expert panel, 7 submitters; last evaluated 2023-11-14). AlphaMissense: likely benign (0.2146); Ultra-rare (popmax 0.0121%, afr); Associated with severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs121908737 · 7 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0121%, afr)

## For patients & families {#patients}

This is a change in the ADA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 7 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.Arg149Gln |
| Coding change (HGVS c.) | c.446G>A |
| MANE Select transcript | [NM_000022](https://www.ncbi.nlm.nih.gov/nuccore/NM_000022) |
| dbSNP | [rs121908737](https://www.ncbi.nlm.nih.gov/snp/rs121908737/) |
| Variant type | single nucleotide variant |
| Location | chr20:44625601-44625601 (GRCh38) |
| ClinVar | [VCV1963](https://www.ncbi.nlm.nih.gov/clinvar/variation/1963/) |

**All HGVS expressions:** `LRG_16:g.31135G>A`, `LRG_16t1:c.446G>A`, `NC_000020.10:g.43254242C>T`, `NC_000020.11:g.44625601C>T`, `NG_007385.1:g.31135G>A`, `NM_000022.4:c.446G>A`, `NM_001322050.2:c.73+855G>A`, `NM_001322051.2:c.446G>A`, `NR_136160.2:n.538G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2146)
- REVEL 0.889 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -14.473 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.593, GERP 0.252, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.9**. 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 **0.0121%** (afr) · FAF95 0.00626% · FAF99 0.00469% · 9/74,646 in the highest group · 34/1,588,694 alleles overall — ultra-rare (popmax 0.0121%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0121% | 8,294 |
| Remaining individuals (not grpmax-eligible) | 0.00488% | 20,490 |
| European (non-Finnish) | 0.00188% | 53,077 |

*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 **149** lies in a UniProt-annotated variant site (in adascid; uncertain significance); a UniProt-annotated variant site (in adascid); 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}

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

**Submitter consensus:** conflicting (5 Uncertain significance, 1 Pathogenic, 1 not provided).

**Submission history:** 7 submissions (1990–2025); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — Severe Combined Immunodeficiency Disease VCEP (adenosine deaminase deficiency). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM5_Supporting`, `BS3_Supporting`.
*Considered but not met:* `PM6`, `PM2`, `PS1`, `PS2`, `PS3`, `PP1`, `PP4`, `PM3`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000022.4(ADA):c.446G>A (p.Arg149Gln) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 149 (p.Arg149Gln).  The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/107374 observed alleles) is 0.000003610 on gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742). However, we can not use this evidence because it has a filter warning (RF). Expressed ADA activity in Escherichia coli strain SO3834 (ADA-deleted) showed 13.0 +- 13.1% of Wild Type ADA activity, belonging to group IV (range: 4.8–28.2). These results indicate that this variant does not impact the protein function (PMID: 9758612, BS3_moderate). At least one additional missense variant was observed as LP according to SCID VCEP specifications version (PM5_supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS3_Supporting, and PM5_Suppoting. (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/ceb546d2-46b3-473c-a5e0-c41a6688ecf0).*
*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 |
| --- | --- | --- | --- | --- |
| ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Uncertain significance | reviewed by expert panel | curation | 2023-11-14 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-03-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-10 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1990-08-01 |
| UniProtKB/Swiss-Prot | not provided | no classification provided | not provided |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-13 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-08 |

## 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, Partial adenosine deaminase deficiency, not specified, not provided, AllHighlyPenetrant, none provided, ADA-SCID, Adenosine Deaminase Deficiency, SCID DUE TO ADA DEFICIENCY, SCID DUE TO ADA DEFICIENCY, EARLY-ONSET.

## Same-residue context {#hotspot}

Residue **149** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ADA p.Arg149Trp](/variant/ada-p-arg149trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ADA variant pages (same residue, condition, or type): [ADA p.Arg149Trp](/variant/ada-p-arg149trp), [ADA p.Arg149=](/variant/ada-p-arg149), [ADA p.Arg149Leu](/variant/ada-p-arg149leu), [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).

### 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 1963). 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.*