# NM_002435.3(MPI):c.1022dup (p.Val342fs)

https://sugi.bio/variant/mpi-p-val342fs

## Summary

**MPI p.Val342fs (c.1022dup)** is classified **Pathogenic/Likely pathogenic** in MPI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-10). Very rare (popmax 0.00402%, afr); Associated with MPI-congenital disorder of glycosylation.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs765310894 · 3 submitters · 1 linked condition · very rare (popmax 0.00402%, afr)

## For patients & families {#patients}

This is a change in the MPI gene that is considered likely disease-causing, submitted by 3 submitters, 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.Val342fs |
| Coding change (HGVS c.) | c.1022dup |
| MANE Select transcript | [NM_002435](https://www.ncbi.nlm.nih.gov/nuccore/NM_002435) |
| dbSNP | [rs765310894](https://www.ncbi.nlm.nih.gov/snp/rs765310894/) |
| Variant type | Duplication |
| Location | chr15:74897182-74897183 (GRCh38) |
| ClinVar | [VCV1368178](https://www.ncbi.nlm.nih.gov/clinvar/variation/1368178/) |

**All HGVS expressions:** `NC_000015.10:g.74897188dup`, `NC_000015.9:g.75189529dup`, `NG_008921.1:g.12120dup`, `NM_001289155.2:c.845-324dup`, `NM_001289156.2:c.872dup`, `NM_001289157.2:c.839dup`, `NM_001330372.2:c.962dup`, `NM_002435.3:c.1022dup`

## 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 6.94, GERP 0.194, phastCons 0.984 — 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 **within the last 50 nt of the penultimate exon (7 of 8, 37 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 27.9**. 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: **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 (gnomAD v4.1): grpmax **0.00402%** (afr) · FAF95 0.00107% · FAF99 0.000496% · 3/74,710 in the highest group · 6/1,613,432 alleles overall — very rare (popmax 0.00402%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00402% | 24,903 |
| Admixed American | 0.00167% | 59,928 |
| South Asian | 0.0011% | 91,042 |
| European (non-Finnish) | 8.48e-05% | 1,179,915 |

*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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-10.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-01 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-06-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-10 |

## 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, CDG Ib, MANNOSEPHOSPHATE ISOMERASE DEFICIENCY, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ib, MPI-CDG, PROTEIN-LOSING ENTEROPATHY-HEPATIC FIBROSIS SYNDROME, MPI DEFICIENCY.

## Similar variants {#similar}

Related MPI variant pages (same residue, condition, or type): [MPI p.Arg56fs](/variant/mpi-p-arg56fs), [MPI p.Leu335fs](/variant/mpi-p-leu335fs), [MPI p.Lys115Ter](/variant/mpi-p-lys115ter), [MPI p.Gln124fs](/variant/mpi-p-gln124fs), [MPI p.Glu236fs](/variant/mpi-p-glu236fs), [MPI p.Gly265fs](/variant/mpi-p-gly265fs), [MPI p.His178fs](/variant/mpi-p-his178fs), [MPI p.Ile249fs](/variant/mpi-p-ile249fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1368178). 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.*