GPAA1

Chr 8AR

glycosylphosphatidylinositol anchor attachment 1

Also known as: GAA1, GPIBD15, hGAA1

NCBI Gene: 8733ENSG00000197858UniProt: O43292

Posttranslational glycosylphosphatidylinositol (GPI) anchor attachment serves as a general mechanism for linking proteins to the cell surface membrane. The protein encoded by this gene presumably functions in GPI anchoring at the GPI transfer step. The mRNA transcript is ubiquitously expressed in both fetal and adult tissues. The anchor attachment protein 1 contains an N-terminal signal sequence, 1 cAMP- and cGMP-dependent protein kinase phosphorylation site, 1 leucine zipper pattern, 2 potential N-glycosylation sites, and 8 putative transmembrane domains. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Glycosylphosphatidylinositol biosynthesis defect 15MIM #617810
AR
721
ClinVar variants
79
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GPAA1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
79 Pathogenic / Likely Pathogenic· 193 VUS of 721 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.98LOEUF
pLI 0.000
Z-score 1.65
OE 0.65 (0.45–0.98)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.87Z-score
OE missense 0.87 (0.80–0.96)
324 obs / 371.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.65 (0.45–0.98)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.80–0.96)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 17 / 26.1Missense obs/exp: 324 / 371.1Syn Z: -0.43

ClinVar Variant Classifications

721 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57
Likely Pathogenic22
VUS193
Likely Benign201
Benign6
Conflicting7
57
Pathogenic
22
Likely Pathogenic
193
VUS
201
Likely Benign
6
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
1
45
0
57
Likely Pathogenic
12
4
6
0
22
VUS
1
173
17
2
193
Likely Benign
0
3
79
119
201
Benign
0
3
2
1
6
Conflicting
—7
Total24184149122486

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

View in ClinVar →

Protein Context — Lollipop Plot

GPAA1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GPAA1-related developmental delay, epilepsy, cerebellar atrophy, and osteopenia

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Glycosylphosphatidylinositol biosynthesis defect 15

MIM #617810

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A Novel Homozygous GPAA1 Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect.
Fontana P et al.·Genes (Basel)
2023Case report
A novel variant in GPAA1, encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes.
Li Y et al.·Hum Genet
2020
Identification and Validation of Prognostically Relevant Gene Signature in Melanoma.
Gao Y et al.·Biomed Res Int
2020
[Glycosylphosphatidylinositol biosynthesis deficiency 15 caused by GPAA1 gene mutation: a rare disease study].
Chen QR et al.·Zhongguo Dang Dai Er Ke Za Zhi
2023Case report
Exploring the genetic etiology of drug-resistant epilepsy: incorporation of exome sequencing into practice.
Mahdiannasser M et al.·Acta Neurol Belg
2022
Glycosylphosphatidylinositol anchor biosynthesis pathway-based biomarker identification with machine learning for prognosis and T cell exhaustion status prediction in breast cancer.
Wu H et al.·Front Immunol
2024
Exome sequencing reveals genetic heterogeneity in consanguineous Pakistani families with neurodevelopmental and neuromuscular disorders.
Bibi A et al.·Am J Med Genet C Semin Med Genet
2024
Genomic profiling of invasive melanoma cell lines by array comparative genomic hybridization.
Koroknai V et al.·Melanoma Res
2016
Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies.
Knaus A et al.·Am J Hum Genet
2019
A host transcriptomic signature for identification of respiratory viral infections in the community.
Almansa R et al.·Eur J Clin Invest
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools