# NM_001385.3(DPYS):c.904C>T (p.Arg302Ter)

https://sugi.bio/variant/dpys-p-arg302ter

## Summary

**DPYS p.Arg302Ter (c.904C>T)** is classified **Pathogenic/Likely pathogenic** in DPYS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-12). Ultra-rare (popmax 0.022%, sas); Associated with dihydropyrimidinuria.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · 2 submitters · 1 linked condition · ultra-rare (popmax 0.022%, sas)

## For patients & families {#patients}

This is a change in the DPYS gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to dihydropyrimidinuria.

*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) | Childhood, Infancy |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | DPYS is a diagnostic-grade gene on 7 Genomics England panels |

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

- Intellectual disability — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Uraciluria — Frequent (79-30%)
- Elevated urinary dihydrouracil level — Frequent (79-30%)
- Elevated urinary dihydrothymine level — Frequent (79-30%)
- Elevated urinary thymine level — Frequent (79-30%)
- Microcephaly — Occasional (29-5%)
- Macrocephaly — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012347/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DPYS](https://sugi.bio/atlas/gene/DPYS/) |
| Protein change (HGVS p.) | p.Arg302Ter |
| Coding change (HGVS c.) | c.904C>T |
| MANE Select transcript | [NM_001385](https://www.ncbi.nlm.nih.gov/nuccore/NM_001385) |
| Variant type | single nucleotide variant |
| Location | chr8:104429591-104429591 (GRCh38) |
| ClinVar | [VCV3902332](https://www.ncbi.nlm.nih.gov/clinvar/variation/3902332/) |

**All HGVS expressions:** `NC_000008.10:g.105441819G>A`, `NC_000008.11:g.104429591G>A`, `NG_008840.2:g.42459C>T`, `NM_001385.3:c.904C>T`

## 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 loss** (Δ 0.27) — consistent with the pathogenic call
- Conservation: phyloP 1.205, GERP -3.77, phastCons 0.993 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.029, pLI 4.0417e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 10**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 36.0**. 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 **0.27**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 46 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.022%** (sas) · FAF95 0.0145% · FAF99 0.0121% · 20/91,082 in the highest group · 110/1,613,970 alleles overall — ultra-rare (popmax 0.022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.022% | 4,554 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,496 |
| African / African-American | 0.00668% | 14,977 |
| European (non-Finnish) | 0.00661% | 15,128 |
| East Asian | 0.00223% | 44,888 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,032 |

*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}

**DPYS** population constraint: LOEUF 1.029, pLI 4.0417e-11, missense-Z 0.14001; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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 **302** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.00, 94% of residues very-high.

**1 experimental structure(s)** (PDB): [2VR2](https://www.rcsb.org/structure/2VR2).

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

*Describes the biological roles of DPYS (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:** DPYS's established molecular role includes dihydropyrimidinase activity.


### Pathways affected {#pathways}

DPYS participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Pyrimidine catabolism](https://reactome.org/content/detail/R-HSA-73621) | curated |

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

**Molecular function:** dihydropyrimidinase activity.

**Biological process:** pyrimidine nucleobase catabolic process, uracil catabolic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-12.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-12 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-03 |

## Associated conditions {#conditions}

[dihydropyrimidinuria](https://sugi.bio/atlas/disease/dihydropyrimidinuria/).

**Reported phenotype names (ClinVar):** Dihydropyrimidinase deficiency, DPYS-related disorders, DPH DEFICIENCY, DPYS DEFICIENCY, dihydropyrimidinuria.

## Same-residue context {#hotspot}

Residue **302** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DPYS p.Arg302Gln](/variant/dpys-p-arg302gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DPYS variant pages (same residue, condition, or type): [DPYS p.Arg302Gln](/variant/dpys-p-arg302gln), [DPYS p.Arg465Ter](/variant/dpys-p-arg465ter), [DPYS p.Arg475Ter](/variant/dpys-p-arg475ter), [DPYS p.Arg490Cys](/variant/dpys-p-arg490cys), [DPYS p.Arg490His](/variant/dpys-p-arg490his), [DPYS p.Gln190Ter](/variant/dpys-p-gln190ter), [DPYS p.Gln334Arg](/variant/dpys-p-gln334arg), [DPYS p.Gln85Ter](/variant/dpys-p-gln85ter).

### 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 3902332). 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.*