MPI

Chr 15AR

mannose phosphate isomerase

Also known as: CDG1B, PMI, PMI1

NCBI Gene: 4351 ENSG00000178802 UniProt: P34949 OMIM: 154550

Phosphomannose isomerase catalyzes the interconversion of fructose-6-phosphate and mannose-6-phosphate, maintaining the supply of D-mannose derivatives required for glycosylation reactions. Mutations cause congenital disorder of glycosylation type Ib, inherited in an autosomal recessive pattern. The pathogenic mechanism involves disruption of protein glycosylation due to impaired mannose metabolism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Phosphomannose isomerase catalyzes the interconversion of fructose-6-phosphate and mannose-6-phosphate and plays a critical role in maintaining the supply of D-mannose derivatives, which are required for most glycosylation reactions. Mutations in the MPI gene were found in patients with carbohydrate-deficient glycoprotein syndrome, type Ib. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Congenital disorder of glycosylation, type IbMIM #602579

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · MPI-congenital disorder of glycosylation · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

942

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.17

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.17LOEUF

pLI 0.000

Z-score 1.03

OE 0.74 (0.48–1.17)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.15Z-score

OE missense 0.97 (0.87–1.09)

219 obs / 225.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.48–1.17)

0≤0.351.4

Missense OE?0.97 (0.87–1.09)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 13 / 17.7Missense obs/exp: 219 / 225.5Syn Z: 0.90

Background carrier burden — how many people carry a rare variant somewhere in MPI?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 95

656 rare PASS variants

Rare truncating (LoF)

1 in 1,100

154 rare PASS variants

Rare synonymous (reference)

1 in 160

254 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MPI. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 1,600
South Asian	~43k	1 in 140	1 in 560
Remaining (unassigned)	~30k	1 in 86	1 in 1,700
European (Finnish)	~27k	1 in 200	≈ 1 in 13,000
Admixed American	~22k	1 in 120	1 in 520
African / African American	~21k	1 in 66	1 in 970
East Asian	~20k	1 in 120	1 in 870
Ashkenazi Jewish	~13k	1 in 290	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 140	≈ 1 in 2,600

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓