# NM_000110.4(DPYD):c.2135del (p.Pro712fs)

https://sugi.bio/variant/dpyd-p-pro712fs

## Summary

**DPYD p.Pro712fs (c.2135del)** is classified **Likely pathogenic** in DPYD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-25). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1064796552 · 1 submitter · 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.

*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 | [DPYD](https://sugi.bio/atlas/gene/DPYD/) |
| Protein change (HGVS p.) | p.Pro712fs |
| Coding change (HGVS c.) | c.2135del |
| MANE Select transcript | [NM_000110](https://www.ncbi.nlm.nih.gov/nuccore/NM_000110) |
| dbSNP | [rs1064796552](https://www.ncbi.nlm.nih.gov/snp/rs1064796552/) |
| Variant type | Deletion |
| Location | chr1:97306221-97306221 (GRCh38) |
| ClinVar | [VCV423651](https://www.ncbi.nlm.nih.gov/clinvar/variation/423651/) |

**All HGVS expressions:** `LRG_722:g.619839del`, `LRG_722t1:c.2135del`, `NC_000001.10:g.97771780del`, `NC_000001.11:g.97306224del`, `NG_008807.2:g.619839del`, `NM_000110.3:c.2135del`, `NM_000110.3:c.2135delC`, `NM_000110.4:c.2135del`, `NR_046590.1:n.164del`

## 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 0.697, GERP -2.5, phastCons 1 — weakly conserved position
- 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 17 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-25.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-07-25 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## 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 423651). 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.*