# NM_000110.4(DPYD):c.1727del (p.Phe576fs)

https://sugi.bio/variant/dpyd-p-phe576fs

## Summary

**DPYD p.Phe576fs (c.1727del)** is classified **Likely pathogenic** in DPYD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-12-28). No gnomAD frequency available for this variant; Associated with dihydropyrimidine dehydrogenase deficiency.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs764584080 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DPYD gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to dihydropyrimidine dehydrogenase 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) | All ages |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DPYD is a diagnostic-grade gene on 10 Genomics England panels |

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

- Reduced dihydropyrimidine dehydrogenase activity — Very frequent (99-80%)
- Uraciluria — Very frequent (99-80%)
- Seizure — Frequent (79-30%)
- Global developmental delay — Frequent (79-30%)
- Specific learning disability — Frequent (79-30%)
- EEG abnormality — Frequent (79-30%)
- Floppy infant — Frequent (79-30%)
- Multifocal epileptiform discharges — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000019/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DPYD](https://sugi.bio/atlas/gene/DPYD/) |
| Protein change (HGVS p.) | p.Phe576fs |
| Coding change (HGVS c.) | c.1727del |
| MANE Select transcript | [NM_000110](https://www.ncbi.nlm.nih.gov/nuccore/NM_000110) |
| dbSNP | [rs764584080](https://www.ncbi.nlm.nih.gov/snp/rs764584080/) |
| Variant type | Deletion |
| Location | chr1:97515739-97515739 (GRCh38) |
| ClinVar | [VCV370256](https://www.ncbi.nlm.nih.gov/clinvar/variation/370256/) |

**All HGVS expressions:** `LRG_722:g.410321del`, `NC_000001.10:g.97981297del`, `NC_000001.11:g.97515741del`, `NG_008807.2:g.410321del`, `NM_000110.3:c.1727delT`, `NM_000110.4:c.1727del`

## 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 2.802, GERP -0.037, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.09, pLI 6.0188e-30. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**DPYD** population constraint: LOEUF 1.09, pLI 6.0188e-30, missense-Z 0.10047; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (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}


AlphaFold model confidence (whole protein): pLDDT 96.23, 95% of residues very-high.

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

*Describes the biological roles of DPYD (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:** DPYD's established molecular role includes dihydropyrimidine dehydrogenase (NADP+) activity.


### Pathways affected {#pathways}

DPYD 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:** dihydropyrimidine dehydrogenase (NADP+) activity, protein homodimerization activity.

**Biological process:** purine nucleobase catabolic process, pyrimidine nucleobase catabolic process, thymine catabolic process, uracil catabolic process, thymidine catabolic process, xenobiotic catabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2015-12-28.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2015-12-28 |

## Associated conditions {#conditions}

[dihydropyrimidine dehydrogenase deficiency](https://sugi.bio/atlas/disease/dihydropyrimidine-dehydrogenase-deficiency/).

**Reported phenotype names (ClinVar):** Dihydropyrimidine dehydrogenase deficiency, DPD DEFICIENCY, DPYD DEFICIENCY, Hereditary Thymine-Uraciluria.

## Similar variants {#similar}

Related DPYD variant pages (same residue, condition, or type): [DPYD c.1977_1983del](/variant/dpyd-c-1977-1983del), [DPYD p.Arg589fs](/variant/dpyd-p-arg589fs), [DPYD p.Arg916fs](/variant/dpyd-p-arg916fs), [DPYD p.Gln860fs](/variant/dpyd-p-gln860fs), [DPYD p.Leu682fs](/variant/dpyd-p-leu682fs), [DPYD p.Lys42_Arg43insTer](/variant/dpyd-p-lys42-arg43inster), [DPYD c.850+23455_1128+8811del](/variant/dpyd-c-850-plus-23455-1128-plus-8811del), [DPYD p.Ala946fs](/variant/dpyd-p-ala946fs).

### 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 370256). 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.*