# NM_000485.3(APRT):c.518TCT[1] (p.Phe174del)

https://sugi.bio/variant/aprt-p-phe174del

## Summary

**APRT p.Phe174del (c.518TCT[1])** is classified **Pathogenic/Likely pathogenic** in APRT (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-09-23). Ultra-rare (popmax 0.0147%, afr); Associated with APRT-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121912681 · 8 submitters · 2 linked conditions · ultra-rare (popmax 0.0147%, afr)

## For patients & families {#patients}

This is a change in the APRT gene that is considered likely disease-causing, submitted by 8 submitters, and is linked to APRT-related disorder.

*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.Phe174del |
| Coding change (HGVS c.) | c.518TCT[1] |
| MANE Select transcript | [NM_000485](https://www.ncbi.nlm.nih.gov/nuccore/NM_000485) |
| dbSNP | [rs121912681](https://www.ncbi.nlm.nih.gov/snp/rs121912681/) |
| Variant type | Microsatellite |
| Location | chr16:88809718-88809720 (GRCh38) |
| ClinVar | [VCV18294](https://www.ncbi.nlm.nih.gov/clinvar/variation/18294/) |

**All HGVS expressions:** `NC_000016.10:g.88809720AAG[1]`, `NC_000016.9:g.88876128AAG[1]`, `NG_008013.1:g.7212TCT[1]`, `NG_028266.1:g.10943AAG[1]`, `NM_000485.2:c.521_523del`, `NM_000485.3:c.518TCT[1]`, `NM_000485.3:c.521_523del`, `NM_001030018.2:c.401-14_401-12del`

## Computational & population evidence {#evidence}

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

- **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 11.665, GERP 1.62, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 16.18**. 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** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.0147%** (afr) · FAF95 0.00814% · FAF99 0.00632% · 11/75,052 in the highest group · 102/1,613,428 alleles overall — ultra-rare (popmax 0.0147%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0147% | 6,823 |
| East Asian | 0.0134% | 7,482 |
| European (non-Finnish) | 0.00644% | 15,526 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,625 |
| Finnish (not grpmax-eligible) | 0.00316% | 31,641 |
| South Asian | 0.0022% | 45,544 |
| Admixed American | 0.00167% | 60,030 |

*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 **174** 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-23.

**Submitter consensus:** conflicting (4 Pathogenic, 3 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 8 submissions (1987–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1987-11-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-07 |
| APRT Deficiency Research Program of the Rare Kidney Stone Consortium, Landspitali, National University Hospital of Iceland | Pathogenic | criteria provided, single submitter | clinical testing | 2020-09-01 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | flagged submission | research | 2023-02-27 |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-23 |
| Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-02-24 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-03 |

## Associated conditions {#conditions}

[APRT-related disorder](https://sugi.bio/atlas/disease/aprt-related-disorder/), [adenine phosphoribosyltransferase deficiency](https://sugi.bio/atlas/disease/adenine-phosphoribosyltransferase-deficiency/).

**Reported phenotype names (ClinVar):** APRT-related disorder, Adenine phosphoribosyltransferase deficiency, See cases, not provided, APRT-related condition, none provided, APRT DEFICIENCY, NEPHROLITHIASIS, DHA, 2,8-dihydroxyadenine urolithiasis, Urolithiasis, dha.

## Similar variants {#similar}

Related APRT variant pages (same residue, condition, or type): [APRT p.Leu97fs](/variant/aprt-p-leu97fs), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 18294). 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.*