# NM_000485.3(APRT):c.321G>A (p.Lys107=)

https://sugi.bio/variant/aprt-p-lys107

## Summary

**APRT p.Lys107= (c.321G>A)** is classified **Uncertain significance** in APRT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-11). Ultra-rare (popmax 0.0117%, nfe); Associated with adenine phosphoribosyltransferase deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs368062984 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0117%, nfe)

## 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 2 submitters, 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.Lys107= |
| Coding change (HGVS c.) | c.321G>A |
| MANE Select transcript | [NM_000485](https://www.ncbi.nlm.nih.gov/nuccore/NM_000485) |
| dbSNP | [rs368062984](https://www.ncbi.nlm.nih.gov/snp/rs368062984/) |
| Variant type | single nucleotide variant |
| Location | chr16:88810423-88810423 (GRCh38) |
| ClinVar | [VCV3014671](https://www.ncbi.nlm.nih.gov/clinvar/variation/3014671/) |

**All HGVS expressions:** `NC_000016.10:g.88810423C>T`, `NC_000016.9:g.88876831C>T`, `NG_008013.1:g.6512G>A`, `NG_028266.1:g.11646C>T`, `NG_134890.1:g.262C>T`, `NM_000485.3:c.321G>A`, `NM_001030018.2:c.321G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.33) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.868, GERP 1.47, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.2**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.24**, acceptor gain **0.00**, donor gain **0.33**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.33**.
- Pangolin: Δ**0.49** (loss), gain 0.11 / loss 0.49. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0117%** (nfe) · FAF95 0.01% · FAF99 0.00948% · 138/1,180,006 in the highest group · 146/1,611,740 alleles overall — ultra-rare (popmax 0.0117%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0117% | 8,551 |
| Finnish (not grpmax-eligible) | 0.00486% | 20,584 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,227 |
| South Asian | 0.0022% | 45,539 |
| African / African-American | 0.00133% | 74,954 |

*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 **107** 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-11.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-19 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-11 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Adenine phosphoribosyltransferase deficiency, not provided, none provided, 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 3014671). 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.*