# NM_001385.3(DPYS):c.1170A>C (p.Pro390=)

https://sugi.bio/variant/dpys-p-pro390

## Summary

**DPYS p.Pro390= (c.1170A>C)** is classified **Uncertain significance** in DPYS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-10). Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs767535896 · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the DPYS 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 | [DPYS](https://sugi.bio/atlas/gene/DPYS/) |
| Protein change (HGVS p.) | p.Pro390= |
| Coding change (HGVS c.) | c.1170A>C |
| MANE Select transcript | [NM_001385](https://www.ncbi.nlm.nih.gov/nuccore/NM_001385) |
| dbSNP | [rs767535896](https://www.ncbi.nlm.nih.gov/snp/rs767535896/) |
| Variant type | single nucleotide variant |
| Location | chr8:104424312-104424312 (GRCh38) |
| ClinVar | [VCV1996397](https://www.ncbi.nlm.nih.gov/clinvar/variation/1996397/) |

**All HGVS expressions:** `NC_000008.10:g.105436540T>G`, `NC_000008.11:g.104424312T>G`, `NG_008840.2:g.47738A>C`, `NM_001385.3:c.1170A>C`

## 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 -1.242, GERP -2.85, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.565**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.25 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/60,010 in the highest group · 2/1,614,030 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,010 |
| European (non-Finnish) | 8.47e-05% | 1,180,016 |

*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 gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **390** lies in a turn.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-10.

**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 | 2023-07-10 |

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

## Similar variants {#similar}

Related DPYS variant pages (same residue, condition, or type): [DPYS c.424-1G>A](/variant/dpys-c-424-minus-1g-a), [DPYS p.Arg302Gln](/variant/dpys-p-arg302gln), [DPYS p.Arg302Ter](/variant/dpys-p-arg302ter), [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).

### 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 1996397). 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.*