PIGA

Chr XXLR

phosphatidylinositol glycan anchor biosynthesis class A

Also known as: GPI3, MCAHS2, NEDEPH, PIG-A, PNH1

NCBI Gene: 5277ENSG00000165195UniProt: P37287

This gene encodes a protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI), the first intermediate in the biosynthetic pathway of GPI anchor. The GPI anchor is a glycolipid found on many blood cells and which serves to anchor proteins to the cell surface. Paroxysmal nocturnal hemoglobinuria, an acquired hematologic disorder, has been shown to result from mutations in this gene. Alternate splice variants have been characterized. A related pseudogene is located on chromosome 12. [provided by RefSeq, Jun 2010]

Primary Disease Associations & Inheritance

Multiple congenital anomalies-hypotonia-seizures syndrome 2MIM #300868
XLR
Neurodevelopmental disorder with epilepsy and hemochromatosisMIM #301072
XLR
Paroxysmal nocturnal hemoglobinuria, somaticMIM #300818
113
ClinVar variants
17
Pathogenic / LP
0.96
pLI score· haploinsufficient
4
Active trials
Clinical Summary— PIGA
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
17 Pathogenic / Likely Pathogenic· 62 VUS of 113 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.30LOEUF
pLI 0.961
Z-score 2.95
OE 0.00 (0.00–0.30)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
2.17Z-score
OE missense 0.56 (0.47–0.65)
105 obs / 188.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.00 (0.00–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.56 (0.47–0.65)
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.0.75
0≤1.21.6
LoF obs/exp: 0 / 10.1Missense obs/exp: 105 / 188.9Syn Z: 1.61

ClinVar Variant Classifications

113 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic4
VUS62
Likely Benign29
Benign3
Conflicting2
13
Pathogenic
4
Likely Pathogenic
62
VUS
29
Likely Benign
3
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
11
0
13
Likely Pathogenic
1
3
0
0
4
VUS
1
54
6
1
62
Likely Benign
0
2
6
21
29
Benign
0
0
2
1
3
Conflicting
—2
Total4592523113

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

View in ClinVar →

Protein Context — Lollipop Plot

PIGA · protein map & ClinVar variants

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

Gene2Phenotype Curations

PIGA-related multiple congenital anomalies-hypotonia-seizures syndrome

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Multiple congenital anomalies-hypotonia-seizures syndrome 2

MIM #300868

Molecular basis of disorder known

X-linked recessive

Neurodevelopmental disorder with epilepsy and hemochromatosis

MIM #301072

Molecular basis of disorder known

X-linked recessive

Paroxysmal nocturnal hemoglobinuria, somatic

MIM #300818

Molecular basis of disorder known

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Paroxysmal nocturnal haemoglobinuria.
Hill A et al.·Nat Rev Dis Primers
2017Review
X-Linked Epilepsies: A Narrative Review.
Bernardo P et al.·Int J Mol Sci
2024Review
Paroxysmal Nocturnal Hemoglobinuria: Biology and Treatment.
Bravo-Perez C et al.·Medicina (Kaunas)
2023Review
When does a PNH clone have clinical significance?
Babushok DV·Hematology Am Soc Hematol Educ Program
2021Review
Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.
Yoshizato T et al.·N Engl J Med
2015
Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.
Gurnari C et al.·J Clin Oncol
2023
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.
Conte F et al.·Int J Mol Sci
2023Review
The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
Burgess R et al.·Ann Neurol
2019
Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry.
Borowitz MJ et al.·Cytometry B Clin Cytom
2010Guideline
Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043-patient-year analysis.
Gurnari C et al.·Blood
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
PIGA variants are associated with focal epilepsy with favorable outcome and the sub-molecular effect.
Zhou M et al.·Seizure
2026
Identification of CNTN2 as a genetic modifier of PIGA-CDG in a family with incomplete penetrance and in Drosophila.
Thorpe HJ et al.·Am J Hum Genet
2025
Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 Caused by a Novel PIGA Variant Not Associated with a Skewed X-Inactivation Pattern.
Gabaldon-Albero A et al.·Genes (Basel)
2024
PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis.
Meuser E et al.·Mol Cancer Res
2024🔓 Open Access
Drosophila models of phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) mirror patient phenotypes.
Thorpe HJ et al.·G3 (Bethesda)
2024🔓 Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Severe Aplastic Anemia

A Trial Comparing Unrelated Donor BMT With IST for Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)

ACTIVE NOT RECRUITING
NCT05600426Phase PHASE3Boston Children's HospitalStarted 2023-01-25
cyclosporineMatched Unrelated Donor Hematopoetic Stem Cell Transplanthorse anti-thymocyte globulin (ATG)
Bone Marrow Failure DisordersVEXAS SyndromeHemoglobinurea, Paroxysmal

Molecular and Clinical Analysis of Bone Marrow Failure: A Secondary Research Study

ENROLLING BY INVITATION
NCT07102849National Heart, Lung, and Blood Institute (NHLBI)Started 2025-09-09
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet
Severe Aplastic Anemia

RACE 2: a Long Term Follow-up of Patients Participating in the RACE Trial

ENROLLING BY INVITATION
NCT05049668European Society for Blood and Marrow TransplantationStarted 2021-10
ATGAM plus CsA with or without Eltrombopag

External Resources

Links to major genomics databases and tools