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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.881 OMIM phenotype

Clinical Summary— PMM2

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Gene-Disease Validity (ClinGen)

hyperinsulinemic hypoglycemia with polycystic kidney disease · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

258 unique Pathogenic / Likely Pathogenic· 253 VUS of 901 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PMM2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePMM2-related congenital disorder of glycosylationLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6647th %ile

GOF

0.5367th %ile

LOF

0.3066th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

901 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic77

Likely Pathogenic181

VUS253

Likely Benign282

Benign39

Conflicting58

Pathogenic

181

Likely Pathogenic

253

VUS

282

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	22	21	0	77
Likely Pathogenic	86	84	11	0	181
VUS	5	144	100	4	253
Likely Benign	0	3	138	141	282
Benign	0	0	38	1	39
Conflicting	—				58
Total	125	253	308	146	890

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

26 pathogenic / likely-pathogenic (of 84) ClinVar copy-number / structural variants overlap PMM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →