# NM_001282225.2(ADA2):c.61A>G (p.Met21Val)

https://sugi.bio/variant/ada2-p-met21val

## Summary

**ADA2 p.Met21Val (c.61A>G)** is classified **Uncertain significance** in ADA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-18). AlphaMissense: likely benign (0.0516); Very rare (popmax 0.0011%, sas); Associated with deficiency of adenosine deaminase 2.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs773893396 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## 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.Met21Val |
| Coding change (HGVS c.) | c.61A>G |
| MANE Select transcript | [NM_001166105](https://www.ncbi.nlm.nih.gov/nuccore/NM_001166105) (variant reported on NM_001282225) |
| dbSNP | [rs773893396](https://www.ncbi.nlm.nih.gov/snp/rs773893396/) |
| Variant type | single nucleotide variant |
| Location | chr22:17209617-17209617 (GRCh38) |
| ClinVar | [VCV1362202](https://www.ncbi.nlm.nih.gov/clinvar/variation/1362202/) |

**All HGVS expressions:** `LRG_1217:g.17238A>G`, `LRG_1217t1:c.61A>G`, `NC_000022.10:g.17690507T>C`, `NC_000022.11:g.17209617T>C`, `NG_033943.1:g.17238A>G`, `NM_001282225.2:c.61A>G`, `NM_001282226.2:c.61A>G`, `NM_001282227.2:c.-47-19A>G`, `NM_001282228.2:c.-47-19A>G`, `NM_001282229.2:c.-38-2327A>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** (0.0516)
- REVEL 0.057 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.796 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.31) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -2.631, GERP -3.15 — fast-evolving / accelerated position
- CADD: **PHRED 0.009**. 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 deltas (raw): acceptor loss **0.31**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.31**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · 1/91,082 in the highest group · 2/1,461,830 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,082 |
| European (non-Finnish) | 8.47e-05% | 1,180,043 |

*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 2022-07-18.

**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 | 2022-07-18 |

## 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, Polyarteritis nodosa, childhoood-onset, Adenosine Deaminase 2 Deficiency, VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME.

## Similar variants {#similar}

Related ADA2 variant pages (same residue, condition, or type): [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), [ADA2 p.Arg312Ter](/variant/ada2-p-arg312ter), [ADA2 p.Asn370Lys](/variant/ada2-p-asn370lys).

### 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 1362202). 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.*