PMM2

Chr 16AR

phosphomannomutase 2

Also known as: CDG1, CDG1a, CDGS, PMI, PMI1, PMM 2

NCBI Gene: 5373 ENSG00000140650 UniProt: O15305 OMIM: 601785

This protein catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is essential for GDP-mannose synthesis and subsequent dolichol-P-oligosaccharide production required for glycoprotein biosynthesis. Autosomal recessive mutations cause congenital disorder of glycosylation type Ia through defects in glycoprotein biosynthesis. The pathogenic mechanism involves dominant-negative effects that disrupt normal protein glycosylation pathways.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Congenital disorder of glycosylation, type IaMIM #212065

Clinical highlights

Gene–disease validity (ClinGen)

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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.88

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.88LOEUF

pLI 0.000

Z-score -1.51

OE 1.41 (1.00–1.88)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.39Z-score

OE missense 1.33 (1.18–1.50)

186 obs / 139.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.41 (1.00–1.88)

0≤0.351.4

Missense OE?1.33 (1.18–1.50)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 22 / 15.6Missense obs/exp: 186 / 139.8Syn Z: -1.24

Background carrier burden — how many people carry a rare variant somewhere in PMM2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 69

441 rare PASS variants

Rare truncating (LoF)

1 in 970

94 rare PASS variants

Rare synonymous (reference)

1 in 200

170 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PMM2. 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 100	1 in 1,100
South Asian	~43k	1 in 78	1 in 1,700
Remaining (unassigned)	~30k	1 in 84	1 in 1,200
European (Finnish)	~27k	1 in 690	1 in 2,400
Admixed American	~22k	1 in 78	1 in 300
African / African American	~21k	1 in 110	1 in 1,500
East Asian	~20k	1 in 100	1 in 990
Ashkenazi Jewish	~13k	1 in 1,900	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 96	≈ 1 in 2,800

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): 5 of 8 coding exons well covered in gnomAD exomes; exons 2, 5, 7 marginal. Genomes: all 8.? see exons ↓