# NM_000022.4(ADA):c.432C>T (p.Phe144=)

https://sugi.bio/variant/ada-p-phe144

## Summary

**ADA p.Phe144= (c.432C>T)** is classified **Likely benign** in ADA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). Very rare (popmax 0.00804%, sas); 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 benign · review: Single submitter · rsID rs374413123 · 1 submitter · 1 linked condition · very rare (popmax 0.00804%, sas)

## For patients & families {#patients}

This is a change in the ADA gene that is classified as likely benign — not considered disease-causing, 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.Phe144= |
| Coding change (HGVS c.) | c.432C>T |
| MANE Select transcript | [NM_000022](https://www.ncbi.nlm.nih.gov/nuccore/NM_000022) |
| dbSNP | [rs374413123](https://www.ncbi.nlm.nih.gov/snp/rs374413123/) |
| Variant type | single nucleotide variant |
| Location | chr20:44625615-44625615 (GRCh38) |
| ClinVar | [VCV1107286](https://www.ncbi.nlm.nih.gov/clinvar/variation/1107286/) |

**All HGVS expressions:** `LRG_16:g.31121C>T`, `NC_000020.10:g.43254256G>A`, `NC_000020.11:g.44625615G>A`, `NG_007385.1:g.31121C>T`, `NM_000022.4:c.432C>T`, `NM_001322050.2:c.73+841C>T`, `NM_001322051.2:c.432C>T`, `NR_136160.2:n.524C>T`

## Computational & population evidence {#evidence}

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

- **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 -0.745, GERP -2.8 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.794**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.32 donor loss), 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 **0.00804%** (sas) · FAF95 0.00373% · FAF99 0.00313% · 7/87,112 in the highest group · 65/1,587,348 alleles overall — very rare (popmax 0.00804%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00814% | 12,286 |
| South Asian (grpmax) | 0.00804% | 12,445 |
| European (non-Finnish) | 0.00446% | 22,439 |
| East Asian | 0.00228% | 43,786 |

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 **144** lies in an α-helix.

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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-30.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-30 |

## 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, Adenosine Deaminase Deficiency, 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, ADA-SCID.

## Similar variants {#similar}

Related ADA variant pages (same residue, condition, or type): [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), [ADA p.Ala329Val](/variant/ada-p-ala329val), [ADA p.Arg149Trp](/variant/ada-p-arg149trp).

### 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 1107286). 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.*