# NM_002435.3(MPI):c.602T>C (p.Leu201Pro)

https://sugi.bio/variant/mpi-p-leu201pro

## Summary

**MPI p.Leu201Pro (c.602T>C)** is classified **Conflicting classifications of pathogenicity** in MPI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-08-02). AlphaMissense: likely pathogenic (0.9757); Absent from gnomAD v4.1; Associated with MPI-congenital disorder of glycosylation.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2064752971 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MPI gene that is of uncertain or conflicting significance (submitters disagree on it), 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.Leu201Pro |
| Coding change (HGVS c.) | c.602T>C |
| MANE Select transcript | [NM_002435](https://www.ncbi.nlm.nih.gov/nuccore/NM_002435) |
| dbSNP | [rs2064752971](https://www.ncbi.nlm.nih.gov/snp/rs2064752971/) |
| Variant type | single nucleotide variant |
| Location | chr15:74893252-74893252 (GRCh38) |
| ClinVar | [VCV1338634](https://www.ncbi.nlm.nih.gov/clinvar/variation/1338634/) |

**All HGVS expressions:** `NC_000015.10:g.74893252T>C`, `NC_000015.9:g.75185593T>C`, `NG_008921.1:g.8184T>C`, `NM_001289155.2:c.602T>C`, `NM_001289156.2:c.452T>C`, `NM_001289157.2:c.487+450T>C`, `NM_001330372.2:c.542T>C`, `NM_002435.3:c.602T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9757)
- REVEL 0.971 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.501 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.943, GERP 2.14, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in MPI (of 2,490 modeled).
- CADD: **PHRED 31.0**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (74,890,074–74,897,727), spanning 7,653 bp. Chi-square p 0.66. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.47 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2021-08-02.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-03-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-02 |

## 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, not provided, none provided, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ib, MPI-CDG, MPI DEFICIENCY, CDG Ib, MANNOSEPHOSPHATE ISOMERASE DEFICIENCY, PROTEIN-LOSING ENTEROPATHY-HEPATIC FIBROSIS SYNDROME.

## Similar variants {#similar}

Related MPI variant pages (same residue, condition, or type): [MPI p.Leu201=](/variant/mpi-p-leu201), [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), [MPI c.488-2A>G](/variant/mpi-c-488-minus-2a-g), [MPI c.844+1G>A](/variant/mpi-c-844-plus-1g-a), [MPI c.845-2A>G](/variant/mpi-c-845-minus-2a-g), [MPI p.Arg219Gln](/variant/mpi-p-arg219gln).

### 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 1338634). 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.*