# NM_000485.3(APRT):c.526_530del (p.Leu176fs)

https://sugi.bio/variant/aprt-p-leu176fs

## Summary

**APRT p.Leu176fs (c.526_530del)** is classified **Pathogenic** in APRT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-09-01). Very rare (popmax 0.0022%, sas); Associated with adenine phosphoribosyltransferase deficiency.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs755380873 · 1 submitter · 1 linked condition · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the APRT gene that is reported as disease-causing, but on limited review, 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.Leu176fs |
| Coding change (HGVS c.) | c.526_530del |
| MANE Select transcript | [NM_000485](https://www.ncbi.nlm.nih.gov/nuccore/NM_000485) |
| dbSNP | [rs755380873](https://www.ncbi.nlm.nih.gov/snp/rs755380873/) |
| Variant type | Deletion |
| Location | chr16:88809711-88809715 (GRCh38) |
| ClinVar | [VCV988023](https://www.ncbi.nlm.nih.gov/clinvar/variation/988023/) |

**All HGVS expressions:** `NC_000016.10:g.88809713_88809717del`, `NC_000016.9:g.88876121_88876125del`, `NG_008013.1:g.7220_7224del`, `NG_028266.1:g.10936_10940del`, `NM_000485.3:c.526_530del`, `NM_001030018.2:c.401-9_401-5del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.01, GERP -2.3, phastCons 0.786 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.789, pLI 4.7393e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (5 of 5)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000137% · 2/91,084 in the highest group · 2/1,461,074 alleles overall — very rare (popmax 0.0022%, sas).

*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 **176** 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-09-01.

**Submitter consensus:** unanimous (1/1 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 | Pathogenic | no assertion criteria provided | literature only | 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.

## Same-residue context {#hotspot}

Residue **176** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [APRT p.Leu176Phe](/variant/aprt-p-leu176phe). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related APRT variant pages (same residue, condition, or type): [APRT p.Leu176Phe](/variant/aprt-p-leu176phe), [APRT p.Thr96fs](/variant/aprt-p-thr96fs), [APRT c.401-40_401-25del](/variant/aprt-c-401-minus-40-401-minus-25del), [APRT p.Glu158del](/variant/aprt-p-glu158del), [APRT p.Glu5fs](/variant/aprt-p-glu5fs), [APRT p.Phe39fs](/variant/aprt-p-phe39fs), [APRT p.Ser175del](/variant/aprt-p-ser175del), [APRT c.184_187+22del](/variant/aprt-c-184-187-plus-22del).

### 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 988023). 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.*