# NM_001282225.2(ADA2):c.989C>G (p.Thr330Ser)

https://sugi.bio/variant/ada2-p-thr330ser

## Summary

**ADA2 p.Thr330Ser (c.989C>G)** is classified **Uncertain significance** in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-06). AlphaMissense: likely benign (0.0875); Very rare (popmax 8.48e-05%, nfe); Associated with deficiency of adenosine deaminase 2.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2062065746 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the ADA2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to deficiency of adenosine deaminase 2.

*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) | Childhood, Infancy |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012383/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADA2](https://sugi.bio/atlas/gene/ADA2/) |
| Protein change (HGVS p.) | p.Thr330Ser |
| Coding change (HGVS c.) | c.989C>G |
| MANE Select transcript | [NM_001166105](https://www.ncbi.nlm.nih.gov/nuccore/NM_001166105) (variant reported on NM_001282225) |
| dbSNP | [rs2062065746](https://www.ncbi.nlm.nih.gov/snp/rs2062065746/) |
| Variant type | single nucleotide variant |
| Location | chr22:17188431-17188431 (GRCh38) |
| ClinVar | [VCV849811](https://www.ncbi.nlm.nih.gov/clinvar/variation/849811/) |

**All HGVS expressions:** `LRG_1217:g.38424C>G`, `LRG_1217t1:c.989C>G`, `NC_000022.10:g.17669321G>C`, `NC_000022.11:g.17188431G>C`, `NG_033943.1:g.38424C>G`, `NM_001282225.2:c.989C>G`, `NM_001282226.2:c.989C>G`, `NM_001282227.2:c.863C>G`, `NM_001282228.2:c.863C>G`, `NM_001282229.2:c.629C>G`, `NM_177405.3:c.266C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0875)
- REVEL 0.138 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.954 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.42, GERP 1.51, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.18**. 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: **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 **8.48e-05%** (nfe) · 1/1,179,328 in the highest group · 1/1,460,980 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**ADA2** population constraint: ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **obsolete deficiency of adenosine deaminase 2** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.04, 47% of residues very-high.

**1 experimental structure(s)** (PDB): [1X41](https://www.rcsb.org/structure/1X41).

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

*Describes the biological roles of ADA2 (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.*


### Pathways affected {#pathways}

ADA2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of WDR5-containing histone-modifying complexes](https://reactome.org/content/detail/R-HSA-9772755) | curated |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |

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

**Biological process:** regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, regulation of cell division, regulation of cell cycle, regulation of tubulin deacetylation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-06 |

## Associated conditions {#conditions}

[deficiency of adenosine deaminase 2](https://sugi.bio/atlas/disease/deficiency-of-adenosine-deaminase-2/).

**Reported phenotype names (ClinVar):** Deficiency of adenosine deaminase 2, Adenosine Deaminase 2 Deficiency, VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME, Polyarteritis nodosa, childhoood-onset.

## Similar variants {#similar}

Related ADA2 variant pages (same residue, condition, or type): [ADA2 p.Thr330Ala](/variant/ada2-p-thr330ala), [ADA2 p.Thr330=](/variant/ada2-p-thr330), [ADA2 c.754-2A>G](/variant/ada2-c-754-minus-2a-g), [ADA2 c.882-2A>G](/variant/ada2-c-882-minus-2a-g), [ADA2 c.973-2A>G](/variant/ada2-c-973-minus-2a-g), [ADA2 p.Arg169Gln](/variant/ada2-p-arg169gln), [ADA2 p.Arg169Trp](/variant/ada2-p-arg169trp), [ADA2 p.Arg306Ter](/variant/ada2-p-arg306ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 849811). 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.*