# NM_000485.3(APRT):c.16_17inv (p.Leu6Arg)

https://sugi.bio/variant/aprt-p-leu6arg

## Summary

**APRT p.Leu6Arg (c.16_17inv)** is classified **Uncertain significance** in APRT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the APRT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [APRT](https://sugi.bio/atlas/gene/APRT/) |
| Protein change (HGVS p.) | p.Leu6Arg |
| Coding change (HGVS c.) | c.16_17inv |
| MANE Select transcript | [NM_000485](https://www.ncbi.nlm.nih.gov/nuccore/NM_000485) |
| Variant type | Inversion |
| Location | chr16:88811883-88811884 (GRCh38) |
| ClinVar | [VCV1995501](https://www.ncbi.nlm.nih.gov/clinvar/variation/1995501/) |

**All HGVS expressions:** `NC_000016.10:g.88811883_88811884inv`, `NC_000016.9:g.88878291_88878292inv`, `NG_008013.1:g.5051_5052inv`, `NG_008667.1:g.50083_50084inv`, `NM_000485.3:c.16_17inv`, `NM_001030018.2:c.16_17inv`

## 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 6.479, GERP 1.1, phastCons 1 — highly conserved position (PP3-type support)
- 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** — the release is built from a substitutions-only source, so it holds no inversion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **6** lies in an α-helix.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-28.

**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 | 2025-04-28 |

**Reported phenotype names (ClinVar):** not provided, none provided.

### 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 1995501). 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.*