# NM_001282225.2(ADA2):c.753G>A (p.Pro251=)

https://sugi.bio/variant/ada2-p-pro251

## Summary

**ADA2 p.Pro251= (c.753G>A)** is classified **Conflicting classifications of pathogenicity** in ADA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-05). Ultra-rare (popmax 0.0174%, afr); Associated with deficiency of adenosine deaminase 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs369924229 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.0174%, afr)

## For patients & families {#patients}

This is a change in the ADA2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, 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.Pro251= |
| Coding change (HGVS c.) | c.753G>A |
| MANE Select transcript | [NM_001282225](https://www.ncbi.nlm.nih.gov/nuccore/NM_001282225) |
| dbSNP | [rs369924229](https://www.ncbi.nlm.nih.gov/snp/rs369924229/) |
| Variant type | single nucleotide variant |
| Location | chr22:17203563-17203563 (GRCh38) |
| ClinVar | [VCV1392821](https://www.ncbi.nlm.nih.gov/clinvar/variation/1392821/) |

**All HGVS expressions:** `LRG_1217:g.23292G>A`, `LRG_1217t1:c.753G>A`, `NC_000022.10:g.17684453C>T`, `NC_000022.11:g.17203563C>T`, `NG_033943.1:g.23292G>A`, `NM_001282225.1:c.753G>A`, `NM_001282225.2:c.753G>A`, `NM_001282226.2:c.753G>A`, `NM_001282227.2:c.627G>A`, `NM_001282228.2:c.627G>A`, `NM_001282229.2:c.393G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.488, GERP 1.06, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 18.84**. 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 **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.32** (loss), gain 0.01 / loss 0.32. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0174%** (afr) · FAF95 0.0103% · FAF99 0.00814% · 13/74,828 in the highest group · 33/1,610,930 alleles overall — ultra-rare (popmax 0.0174%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0174% | 5,756 |
| East Asian | 0.00668% | 14,961 |
| Remaining individuals (not grpmax-eligible) | 0.00482% | 20,757 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,594 |
| Admixed American | 0.00167% | 59,962 |
| European (non-Finnish) | 0.00102% | 98,241 |

*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 gene assoc. with recessive phenotype, triplosensitivity 0/3. *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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-05.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic, 1 Uncertain significance).

**Submission history:** 4 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-05 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-05 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Deficiency of adenosine deaminase 2, not provided, Sneddon syndrome, none provided, VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME, Polyarteritis nodosa, childhoood-onset, Adenosine Deaminase 2 Deficiency, Idiopathic livedo reticularis with systemic involvement, LIVEDO RETICULARIS AND CEREBROVASCULAR ACCIDENTS.

## Same-residue context {#hotspot}

Residue **251** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ADA2 p.Pro251Leu](/variant/ada2-p-pro251leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ADA2 variant pages (same residue, condition, or type): [ADA2 p.Pro251Leu](/variant/ada2-p-pro251leu), [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).

### 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 2026-10-14); 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 1392821). 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.*