# NM_000485.3(APRT):c.58C>T (p.Pro20Ser)

https://sugi.bio/variant/aprt-p-pro20ser

## Summary

**APRT p.Pro20Ser (c.58C>T)** is classified **Likely pathogenic** in APRT (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-01). AlphaMissense: likely pathogenic (0.9464); No allele count reported in gnomAD v4.1 (AN 1,572,284); Associated with adenine phosphoribosyltransferase deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1909160707 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,572,284)

## For patients & families {#patients}

This is a change in the APRT gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to adenine phosphoribosyltransferase 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) | Adolescent, Adult, Childhood, Elderly, Infancy |
| Prevalence | 1-9 / 100 000 (Specific population) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | APRT is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Adenine phosphoribosyltransferase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Renal insufficiency — Frequent (79-30%)
- Proteinuria — Frequent (79-30%)
- Nephrolithiasis — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Acute kidney injury — Frequent (79-30%)
- Chronic kidney disease — Frequent (79-30%)
- Dysuria — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000546/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [APRT](https://sugi.bio/atlas/gene/APRT/) |
| Protein change (HGVS p.) | p.Pro20Ser |
| Coding change (HGVS c.) | c.58C>T |
| MANE Select transcript | [NM_000485](https://www.ncbi.nlm.nih.gov/nuccore/NM_000485) |
| dbSNP | [rs1909160707](https://www.ncbi.nlm.nih.gov/snp/rs1909160707/) |
| Variant type | single nucleotide variant |
| Location | chr16:88811842-88811842 (GRCh38) |
| ClinVar | [VCV988032](https://www.ncbi.nlm.nih.gov/clinvar/variation/988032/) |

**All HGVS expressions:** `NC_000016.10:g.88811842G>A`, `NC_000016.9:g.88878250G>A`, `NG_008013.1:g.5093C>T`, `NG_008667.1:g.50125C>T`, `NM_000485.3:c.58C>T`, `NM_001030018.2:c.58C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9464) — concordant with the pathogenic call
- REVEL 0.866 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.589 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.099, GERP 1.18, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.7**. 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.*
- Regional missense constraint: **o/e 1.26** across the covering region of the MANE Select transcript (88,809,701–88,811,899), spanning 2,198 bp. Chi-square p 5.8e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **no allele count reported in gnomAD v4.1 (AN 1,572,284)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**APRT** population constraint: LOEUF 1.789, pLI 4.7393e-11, missense-Z -1.8254. *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 **20** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 96.91, 96% of residues very-high.

**16 experimental structure(s)** (PDB): [1ORE](https://www.rcsb.org/structure/1ORE), [1ZN7](https://www.rcsb.org/structure/1ZN7), [1ZN8](https://www.rcsb.org/structure/1ZN8), [1ZN9](https://www.rcsb.org/structure/1ZN9), [4X44](https://www.rcsb.org/structure/4X44), [4X45](https://www.rcsb.org/structure/4X45) — incl. mutant structure 4X44.

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

*Describes the biological roles of APRT (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:** APRT's established molecular role includes adenine phosphoribosyltransferase activity. In Reactome, APRT is annotated in disease pathway(s) including **Defective APRT disrupts adenine salvage**.

**Disease mechanism (Reactome):** APRT loss or alteration is curated in [Defective APRT disrupts adenine salvage](https://reactome.org/content/detail/R-HSA-9734195).

### Pathways affected {#pathways}

APRT participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective APRT disrupts adenine salvage](https://reactome.org/content/detail/R-HSA-9734195) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Purine salvage](https://reactome.org/content/detail/R-HSA-74217) | curated |

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

**Molecular function:** adenine phosphoribosyltransferase activity, AMP binding.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-09-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| APRT Deficiency Research Program of the Rare Kidney Stone Consortium, Landspitali, National University Hospital of Iceland | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-09-01 |

## Associated conditions {#conditions}

[adenine phosphoribosyltransferase deficiency](https://sugi.bio/atlas/disease/adenine-phosphoribosyltransferase-deficiency/).

**Reported phenotype names (ClinVar):** Adenine phosphoribosyltransferase deficiency, APRT DEFICIENCY, NEPHROLITHIASIS, DHA, Urolithiasis, dha, 2,8-dihydroxyadenine urolithiasis.

## Similar variants {#similar}

Related APRT variant pages (same residue, condition, or type): [APRT p.Arg67Gln](/variant/aprt-p-arg67gln), [APRT p.Arg67Ter](/variant/aprt-p-arg67ter), [APRT p.Arg87Ter](/variant/aprt-p-arg87ter), [APRT p.Asp65Val](/variant/aprt-p-asp65val), [APRT p.Gly133Arg](/variant/aprt-p-gly133arg), [APRT p.Gly63Asp](/variant/aprt-p-gly63asp), [APRT p.Met1Ile](/variant/aprt-p-met1ile), [APRT p.Met1Val](/variant/aprt-p-met1val).

### 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 988032). 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.*