GMPPA

Chr 2

GDP-mannose pyrophosphorylase A

Also known as: AAMR

NCBI Gene: 29926 ENSG00000144591 UniProt: Q96IJ6

The protein functions as a regulatory subunit of the GDP-mannose pyrophosphorylase complex, reducing GMPPB catalytic activity and mediating allosteric feedback inhibition to regulate GDP-mannose levels required for N-linked oligosaccharide synthesis. Autosomal recessive mutations cause alacrima, achalasia, and impaired intellectual development syndrome through disrupted glycosylation pathways.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene is thought to encode a GDP-mannose pyrophosphorylase. This enzyme catalyzes the reaction which converts mannose-1-phosphate and GTP to GDP-mannose which is involved in the production of N-linked oligosaccharides. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.94

Clinical Summary— GMPPA

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Gene-Disease Validity (ClinGen)

alacrima, achalasia, and intellectual disability syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

17 unique Pathogenic / Likely Pathogenic· 77 VUS of 196 total submissions

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GeneReview available — GMPPA

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.79

OE 0.63 (0.43–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.21Z-score

OE missense 0.79 (0.70–0.89)

205 obs / 259.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.43–0.94)

0≤0.351.4

Missense OE?0.79 (0.70–0.89)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 17 / 27.0Missense obs/exp: 205 / 259.9Syn Z: 0.50

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic7

VUS77

Likely Benign71

Benign14

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	2	0	0	10
Likely Pathogenic	7	0	0	0	7
VUS	1	73	3	0	77
Likely Benign	0	5	31	35	71
Benign	0	0	12	2	14
Conflicting	—				4
Total	16	80	46	37	183

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap GMPPA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →