# NM_002435.3(MPI):c.130_133dup (p.Pro45fs)

https://sugi.bio/variant/mpi-p-pro45fs

## Summary

**MPI p.Pro45fs (c.130_133dup)** is classified **Likely pathogenic** in MPI (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). No gnomAD frequency available for this variant; Associated with MPI-congenital disorder of glycosylation.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2505811546 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MPI gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to MPI-congenital disorder of glycosylation.

*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) | Infancy, Neonatal |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MPI is a diagnostic-grade gene on 11 Genomics England panels |

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

- Abnormal enzyme/coenzyme activity — Obligate (100%)
- Hepatic fibrosis — Very frequent (99-80%)
- Diarrhea — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)
- Hypoalbuminemia — Very frequent (99-80%)
- Abnormality of the coagulation cascade — Very frequent (99-80%)
- Reduced antithrombin antigen — Very frequent (99-80%)
- Hyperinsulinemic hypoglycemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009830/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MPI](https://sugi.bio/atlas/gene/MPI/) |
| Protein change (HGVS p.) | p.Pro45fs |
| Coding change (HGVS c.) | c.130_133dup |
| MANE Select transcript | [NM_002435](https://www.ncbi.nlm.nih.gov/nuccore/NM_002435) |
| dbSNP | [rs2505811546](https://www.ncbi.nlm.nih.gov/snp/rs2505811546/) |
| Variant type | Duplication |
| Location | chr15:74890638-74890639 (GRCh38) |
| ClinVar | [VCV3239738](https://www.ncbi.nlm.nih.gov/clinvar/variation/3239738/) |

**All HGVS expressions:** `NC_000015.10:g.74890640_74890643dup`, `NC_000015.9:g.75182981_75182984dup`, `NG_008921.1:g.5572_5575dup`, `NG_008921.2:g.5600_5603dup`, `NM_001289155.2:c.130_133dup`, `NM_001289156.2:c.-7+551_-7+554dup`, `NM_001289157.2:c.130_133dup`, `NM_001330372.2:c.70_73dup`, `NM_002435.3:c.130_133dup`

## 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 11.136, GERP 2.29, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.04, pLI 9.3378e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 8**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**MPI** population constraint: LOEUF 1.04, pLI 9.3378e-10, missense-Z 0.59212. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **MPI-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.50, 97% of residues very-high.

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

*Describes the biological roles of MPI (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:** MPI's established molecular role includes mannose-6-phosphate isomerase activity. In Reactome, MPI is annotated in disease pathway(s) including **Defective MPI causes MPI-CDG**.

**Disease mechanism (Reactome):** MPI loss or alteration is curated in [Defective MPI causes MPI-CDG](https://reactome.org/content/detail/R-HSA-4043916).

### Pathways affected {#pathways}

MPI participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective MPI causes MPI-CDG](https://reactome.org/content/detail/R-HSA-4043916) | curated |
| [Synthesis of GDP-mannose](https://reactome.org/content/detail/R-HSA-446205) | curated |

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

**Molecular function:** mannose-6-phosphate isomerase activity.

**Biological process:** mannose to fructose-6-phosphate catabolic process, obsolete GDP-D-mannose biosynthetic process from fructose-6-phosphate.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-05 |

## Associated conditions {#conditions}

[MPI-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/mpi-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** MPI-congenital disorder of glycosylation, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ib, CDG Ib, MANNOSEPHOSPHATE ISOMERASE DEFICIENCY, MPI DEFICIENCY, PROTEIN-LOSING ENTEROPATHY-HEPATIC FIBROSIS SYNDROME, MPI-CDG.

## Same-residue context {#hotspot}

Residue **45** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MPI p.Pro45_Tyr46insTer](/variant/mpi-p-pro45-tyr46inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPI variant pages (same residue, condition, or type): [MPI p.Pro45_Tyr46insTer](/variant/mpi-p-pro45-tyr46inster), [MPI p.Arg56fs](/variant/mpi-p-arg56fs), [MPI p.Leu335fs](/variant/mpi-p-leu335fs), [MPI p.Lys115Ter](/variant/mpi-p-lys115ter), [MPI p.Val342fs](/variant/mpi-p-val342fs), [MPI p.Gln124fs](/variant/mpi-p-gln124fs), [MPI p.Glu236fs](/variant/mpi-p-glu236fs), [MPI p.Gly265fs](/variant/mpi-p-gly265fs).

### 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 3239738). 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.*