# NM_002435.3(MPI):c.1017_1024delinsACCCCTT (p.Asp339fs)

https://sugi.bio/variant/mpi-p-asp339fs

## Summary

**MPI p.Asp339fs (c.1017_1024delinsACCCCTT)** is classified **Likely pathogenic** in MPI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-02). No gnomAD frequency available for this variant; Associated with MPI-congenital disorder of glycosylation.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs2505829538 · 2 submitters · 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 2 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.Asp339fs |
| Coding change (HGVS c.) | c.1017_1024delinsACCCCTT |
| MANE Select transcript | [NM_002435](https://www.ncbi.nlm.nih.gov/nuccore/NM_002435) |
| dbSNP | [rs2505829538](https://www.ncbi.nlm.nih.gov/snp/rs2505829538/) |
| Variant type | Indel |
| Location | chr15:74897183-74897190 (GRCh38) |
| ClinVar | [VCV2676655](https://www.ncbi.nlm.nih.gov/clinvar/variation/2676655/) |

**All HGVS expressions:** `NC_000015.10:g.74897183_74897190delinsACCCCTT`, `NC_000015.9:g.75189524_75189531delinsACCCCTT`, `NG_008921.1:g.12115_12122delinsACCCCTT`, `NG_008921.2:g.12143_12150delinsACCCCTT`, `NM_001289155.2:c.845-329_845-322delinsACCCCTT`, `NM_001289156.2:c.867_874delinsACCCCTT`, `NM_001289157.2:c.834_841delinsACCCCTT`, `NM_001330372.2:c.957_964delinsACCCCTT`, `NM_002435.2:c.1017_1024delCCCCCCTGinsACCCCTT`, `NM_002435.3:c.1017_1024delinsACCCCTT`

## 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 -0.061, GERP -4.77, phastCons 0.617 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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, 36 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-02.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-18 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-02 |

## 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, PROTEIN-LOSING ENTEROPATHY-HEPATIC FIBROSIS SYNDROME, MPI DEFICIENCY, MPI-CDG.

## Similar variants {#similar}

Related MPI variant pages (same residue, condition, or type): [MPI p.Asp339=](/variant/mpi-p-asp339), [MPI c.345+15_345+16delinsAT](/variant/mpi-c-345-plus-15-345-plus-16delinsat), [MPI p.Asn273fs](/variant/mpi-p-asn273fs), [MPI p.Tyr314_Ser317delinsTer](/variant/mpi-p-tyr314-ser317delinster), [MPI p.Leu62Ile](/variant/mpi-p-leu62ile), [MPI c.145-1G>C](/variant/mpi-c-145-minus-1g-c), [MPI c.16+2T>C](/variant/mpi-c-16-plus-2t-c), [MPI c.488-1G>C](/variant/mpi-c-488-minus-1g-c).

### 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 2676655). 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.*