# NM_001025389.2(AMPD3):c.573G>A (p.Pro191=)

https://sugi.bio/variant/ampd3-p-pro191

## Summary

**AMPD3 p.Pro191= (c.573G>A)** is classified **Benign** in AMPD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2018-01-12). Common (popmax 28%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Erythrocyte AMP deaminase deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs16907852 · 4 submitters · 1 linked condition · common (popmax 28%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the AMPD3 gene that is classified as benign — not considered disease-causing, submitted by 4 submitters, and is linked to Erythrocyte AMP 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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AMPD3](https://sugi.bio/atlas/gene/AMPD3/) |
| Protein change (HGVS p.) | p.Pro191= |
| Coding change (HGVS c.) | c.573G>A |
| MANE Select transcript | [NM_001025389](https://www.ncbi.nlm.nih.gov/nuccore/NM_001025389) |
| dbSNP | [rs16907852](https://www.ncbi.nlm.nih.gov/snp/rs16907852/) |
| Variant type | single nucleotide variant |
| Location | chr11:10482209-10482209 (GRCh38) |
| ClinVar | [VCV93471](https://www.ncbi.nlm.nih.gov/clinvar/variation/93471/) |

**All HGVS expressions:** `NC_000011.10:g.10482209G>A`, `NC_000011.9:g.10503756G>A`, `NG_012041.1:g.36533G>A`, `NM_000480.3:c.600G>A`, `NM_001025389.2:c.573G>A`, `NM_001025390.2:c.594G>A`, `NM_001172430.1:c.573G>A`, `NM_001172431.2:c.96G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 28%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -5.057, GERP -3.78 — fast-evolving / accelerated position
- CADD: **PHRED 2.861**. 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 **28%** (afr) · FAF95 27.7% · FAF99 27.6% · 21,001/74,968 in the highest group · 152,969/1,612,012 alleles overall — common (popmax 28%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 28% | 4 |
| Ashkenazi Jewish (not grpmax-eligible) | 11.5% | 9 |
| Middle Eastern | 10.4% | 10 |
| Remaining individuals (not grpmax-eligible) | 9.89% | 10 |
| European (non-Finnish) | 8.89% | 11 |
| Finnish (not grpmax-eligible) | 8.65% | 12 |
| South Asian | 7.63% | 13 |
| Admixed American | 7.54% | 13 |
| Amish (not grpmax-eligible) | 3.73% | 27 |
| East Asian | 0.0869% | 1,150 |

*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}

**AMPD3** population constraint: LOEUF 0.817, pLI 1.5297e-12, missense-Z 2.0819. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **191** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 85.74, 68% of residues very-high.

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

*Describes the biological roles of AMPD3 (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}

AMPD3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Purine salvage](https://reactome.org/content/detail/R-HSA-74217) | curated |

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-01-12.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2013–2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-11-11 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2013-11-20 |

## Associated conditions {#conditions}

[Erythrocyte AMP deaminase deficiency](https://sugi.bio/atlas/disease/erythrocyte-amp-deaminase-deficiency/).

**Reported phenotype names (ClinVar):** Erythrocyte AMP deaminase deficiency, not specified, AMPD3-related disorder, not provided, AllHighlyPenetrant, AMPD3-related condition, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related AMPD3 variant pages (same residue, condition, or type): [AMPD3 p.Pro191Leu](/variant/ampd3-p-pro191leu), [AMPD3 c.1135-5C>A](/variant/ampd3-c-1135-minus-5c-a), [AMPD3 c.1135-6C>G](/variant/ampd3-c-1135-minus-6c-g), [AMPD3 c.1267-3C>T](/variant/ampd3-c-1267-minus-3c-t), [AMPD3 c.*287T>C](/variant/ampd3-c-star-287t-c), [AMPD3 c.*75C>T](/variant/ampd3-c-star-75c-t), [AMPD3 p.Ala141=](/variant/ampd3-p-ala141), [AMPD3 p.Arg426Trp](/variant/ampd3-p-arg426trp).

### 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 93471). 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.*