PIGA

Summary

PIGA (phosphatidylinositol glycan anchor biosynthesis class A, HGNC:8957) is a protein-coding gene on chromosome Xp22.2, encoding Phosphatidylinositol N-acetylglucosaminyltransferase subunit A (P37287). Catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis.

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.

Source: NCBI Gene 5277 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 484 total — 21 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 274
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002641

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8957
Approved symbol	PIGA
Name	phosphatidylinositol glycan anchor biosynthesis class A
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Aliases	GPI3, PIG-A
Ensembl gene	ENSG00000165195
Ensembl biotype	protein_coding
OMIM	311770
Entrez	5277

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000333590, ENST00000463173, ENST00000474662, ENST00000475746, ENST00000482148, ENST00000542278, ENST00000634286, ENST00000634484, ENST00000634582, ENST00000634640, ENST00000635045, ENST00000635480, ENST00000635543, ENST00000635598, ENST00000635631, ENST00000637296, ENST00000637626, ENST00000637799, ENST00000638131

RefSeq mRNA: 2 — MANE Select: NM_002641 NM_002641, NM_020473

CCDS: CCDS14165, CCDS48086

Canonical transcript exons

ENST00000333590 — 6 exons

Exon	Start	End
ENSE00001294155	15331216	15331992
ENSE00001910326	15335501	15335523
ENSE00002212797	15319456	15321772
ENSE00003486162	15324665	15324871
ENSE00003500267	15325020	15325152
ENSE00003660733	15325914	15326046

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 93.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.5377 / max 99.8710, expressed in 1505 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198523	5.5377	1505

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.25	gold quality
mucosa of stomach	UBERON:0001199	90.46	gold quality
endometrium epithelium	UBERON:0004811	90.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.98	gold quality
islet of Langerhans	UBERON:0000006	88.84	gold quality
oocyte	CL:0000023	87.99	gold quality
upper lobe of left lung	UBERON:0008952	87.42	gold quality
right lung	UBERON:0002167	87.36	gold quality
calcaneal tendon	UBERON:0003701	87.28	gold quality
lower lobe of lung	UBERON:0008949	87.25	gold quality
monocyte	CL:0000576	87.23	gold quality
upper lobe of lung	UBERON:0008948	87.03	gold quality
mononuclear cell	CL:0000842	86.86	gold quality
leukocyte	CL:0000738	86.07	gold quality
skin of abdomen	UBERON:0001416	86.07	gold quality
palpebral conjunctiva	UBERON:0001812	85.80	gold quality
cartilage tissue	UBERON:0002418	85.56	gold quality
body of pancreas	UBERON:0001150	85.53	gold quality
pancreas	UBERON:0001264	85.51	gold quality
lung	UBERON:0002048	85.26	gold quality
upper leg skin	UBERON:0004262	83.27	gold quality
esophagus squamous epithelium	UBERON:0006920	83.04	gold quality
skin of leg	UBERON:0001511	82.86	gold quality
zone of skin	UBERON:0000014	82.83	gold quality
rectum	UBERON:0001052	82.63	gold quality
colonic epithelium	UBERON:0000397	82.21	gold quality
bone marrow	UBERON:0002371	82.10	gold quality
esophagus mucosa	UBERON:0002469	82.10	gold quality
lower esophagus mucosa	UBERON:0035834	81.53	gold quality
body of stomach	UBERON:0001161	81.44	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1

miRNA regulators (miRDB)

188 targeting PIGA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 37)

• Molecular testing for mutations in the PIG-A gene can serve as a confirmation test of paroxysmal nocturnal hemoglobinuria. (PMID:12037021)
• Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro allows paroxysmal nocturnal hemoglobinuria clones to escape immune attack. (PMID:12130519)
• PIG-A gene abnormality in precursor cells and changes of expression of GPI-anchored protein and contribution of paroxysmal nocturnal hemoglobinuria clones with PIG-A gene abnormalities among various cell lineages during differentiation and maturation (PMID:12411324)
• The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria reveals a high incidence of multiple mutations and evidence of a mutational hot spot. (PMID:12424196)
• the PIG-A mutations in paroxysmal nocturnal hemoglobinuria patients (PMID:15625823)
• PIG-A mutations are relatively common in normal hematopoiesis (PMID:15687243)
• review of the clinical and biological relevance of PIG-A mutations in paroxysmal nocturnal hemoglobinuria, aplastic anemia and healthy controls [review] (PMID:16923549)
• In patients with paroxysmal nocturnal hemoglobinuria, it is very unlikely that more than one PIG-A mutated clone arises at the level of the hematopoietic stem cells. (PMID:17823237)
• PIG-A mutations contribute to clonal expansion in PNH by conferring a survival advantage to hematopoietic progenitors under proapoptotic stresses. (PMID:19013003)
• Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked PIGA gene. (PMID:19074066)
• loss of PIG-A or a combination of genes within the 0.5 Mb commonly deleted region leads to a phenotype capable of avoiding immune surveillance, but is not inherently malignant. (PMID:21116280)
• An X chromosome exome next-generation sequencing screen identified a single nonsense PIGA mutation. (PMID:22305531)
• The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells. (PMID:22315493)
• the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism. (PMID:24259288)
• Our data strongly suggest that the early frameshift mutation in PIGA produces a truncated hypomorph, which is sufficient to rescue the lethality in males but not the MCAHS2-like phenotype. (PMID:24357517)
• The results of this study confirmed that PIGA mutations are one genetic cause of early-onset epileptic encephalopathies, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE. (PMID:24706016)
• This case reports on a new missense PIGA germline mutation in a Chinese male infant presenting with developmental arrest and multisystemic disorders. (PMID:25885527)
• A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2. (PMID:26545172)
• Pig-a MFs as measured by the RBC Pig-a assay for the ENU-treated group increased in a time-dependent manner with the maximum value at week 4; however, those using the PIGRET assay reached comparable values at week 1 (PMID:27931808)
• The study established a human induced pluripotent stem cell (hiPSC) model containing the PIGAc.1234C>T mutation to study the effects of a hypomorphic allele of PIGA on neuronal development. Neuronal differentiation from neural progenitor cells generated by embryoid bodie formation in PIGAc.1234C>T is significantly impaired with decreased proliferation, aberrant synapse formation and abnormal membrane depolarization. (PMID:28441409)
• This polyclonal mutational landscape in the PIGA gene was also found in CD52(-) T cells present. (PMID:29427418)
• We used the peripheral blood micronucleus assay to evaluate the chromosomal damage, and Pig-a gene mutation assay and gpt gene mutation assay to examine the mutagenicity of BDE-47. (PMID:29462428)
• Clonal PIGA mosaicism and dynamics in paroxysmal nocturnal hemoglobinuria. (PMID:29749402)
• A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2) family pedigree via whole-exome sequencing. (PMID:29974678)
• REVIEW: A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl-phosphatidyl-inositol -specific auto-immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. (PMID:29974931)
• The presence of PIGA mutations in approximately 80% of PNH patients. No detection of any phenotypic differences between patients with and without PIGA mutation, it could not fully explain the clonal expansion of PNH cells based on PIGA mutation alone. (PMID:31037862)
• Identification of acquired PIGA mutations and additional variants by next-generation sequencing in paroxysmal nocturnal hemoglobinuria. (PMID:32359022)
• Lessons learned from 40 novel PIGA patients and a review of the literature. (PMID:32452540)
• PIGA-related epileptic encephalopathy demonstrating intrafamilial phenotypic heterogeneity. (PMID:32562213)
• Early-onset epileptic encephalopathy related to germline PIGA mutations: A series of 5 cases. (PMID:32694024)
• Mutations in PIGA cause a CD52-/GPI-anchor-deficient phenotype complicating alemtuzumab treatment in T-cell prolymphocytic leukemia. (PMID:32875608)
• Evaluation of PIG-A-mutated granulocytes and ex-vivo binucleated micronucleated lymphocytes frequencies after breast cancer radiotherapy in humans. (PMID:33169419)
• Implication of PIGA genotype on erythrocytes phenotype in Paroxysmal Nocturnal Hemoglobinuria. (PMID:33483614)
• Constitutional PIGA mutations cause a novel subtype of hemochromatosis in patients with neurologic dysfunction. (PMID:34875027)
• PIG-A gene mutation as a mutagenicity biomarker among coke oven workers. (PMID:37271276)
• Congenital diaphragmatic hernia in siblings with PIGA-related congenital disorder of glycosylation. (PMID:37589195)
• PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis. (PMID:38546397)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	piga	ENSDARG00000041040
mus_musculus	Piga	ENSMUSG00000031381
rattus_norvegicus	Piga	ENSRNOG00000003554
drosophila_melanogaster	PIG-A	FBGN0034270
caenorhabditis_elegans		WBGENE00008431

Paralogs (3): ALG2 (ENSG00000119523), GLT1D1 (ENSG00000151948), ALG11 (ENSG00000253710)

Protein

Protein identifiers

Phosphatidylinositol N-acetylglucosaminyltransferase subunit A — P37287 (reviewed: P37287)

Alternative names: GlcNAc-PI synthesis protein, Phosphatidylinositol-glycan biosynthesis class A protein

All UniProt accessions (10): A0A0U1RQF5, A0A0U1RQM9, A0A0U1RQW8, A0A0U1RRE8, A0A1B0GU19, A0A1B0GVE5, A0A2K4ZA02, A8K382, B3KUV7, P37287

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis.

Subunit / interactions. Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2. Within the complex, interacts with PIGH. Interacts with PIGC, PIGP, PIGQ and DPM2. Interacts directly with PIGY; this interaction regulates glycosylphosphatidylinositol-N-acetylglucosaminyltransferase activity. Interacts with PIGQ.

Subcellular location. Rough endoplasmic reticulum membrane.

Disease relevance. Paroxysmal nocturnal hemoglobinuria 1 (PNH1) [MIM:300818] A disorder characterized by hemolytic anemia with hemoglobinuria, thromboses in large vessels, and a deficiency in hematopoiesis. Red blood cell breakdown with release of hemoglobin into the urine is manifested most prominently by dark-colored urine in the morning. Disease susceptibility is associated with variants affecting the gene represented in this entry. Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) [MIM:300868] An X-linked recessive developmental disorder characterized by dysmorphic features, neonatal hypotonia, myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Most affected individuals die in infancy. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with epilepsy and hemochromatosis (NEDEPH) [MIM:301072] An X-liked recessive disorder characterized by severe developmental delay, intellectual disability, early-onset epilepsy, and early systemic iron overload resulting in juvenile-onset hemochromatosis. Variable additional features may include joint contractures, visual or hearing impairment, and skin abnormalities. The disease is caused by variants affecting the gene represented in this entry. PIGA deficiency causes disruption of iron homeostasis, due to failure to attach GPI anchors to hemojuvelin (HJV), a BMP coreceptor that regulates hepcidin (HAMP) expression. HAMP is an essential regulator of iron absorption and distribution across tissues. PIGA-deficient cells lack hemojuvelin surface expression and show significantly lower HAMP mRNA levels compared to control cells.

Pathway. Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor biosynthesis.

Similarity. Belongs to the glycosyltransferase group 1 family. Glycosyltransferase 4 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P37287-1	1	yes
P37287-2	2
P37287-3	3

RefSeq proteins (2): NP_002632, NP_065206 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001296	Glyco_trans_1	Domain
IPR013234	PIGA_GPI_anchor_biosynthesis	Domain
IPR039507	PIG-A/GPI3	Family

Pfam: PF00534, PF08288

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + UDP-N-acetyl-alpha-D-glucosamine = a 6-(N-acetyl-alpha-D-glucosaminyl)-1-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol + UDP + H(+) (RHEA:14789)

UniProt features (31 total): sequence variant 20, splice variant 3, topological domain 2, modified residue 2, chain 1, transmembrane region 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P37287-F1	86.22	0.70

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 21, 24

Glycosylation sites (1): 467

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-162710	Synthesis of glycosylphosphatidylinositol (GPI)

MSigDB gene sets: 746 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, TGCACTT_MIR519C_MIR519B_MIR519A, MODULE_45, REACTOME_SYNTHESIS_OF_GLYCOSYLPHOSPHATIDYLINOSITOL_GPI, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GGCNKCCATNK_UNKNOWN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, TTGGGAG_MIR150, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS

GO Biological Process (3): GPI anchor biosynthetic process (GO:0006506), cellular response to leukemia inhibitory factor (GO:1990830), lipid metabolic process (GO:0006629)

GO Molecular Function (5): UDP-glycosyltransferase activity (GO:0008194), phosphatidylinositol N-acetylglucosaminyltransferase activity (GO:0017176), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (4): glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex (GO:0000506), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational modification: synthesis of GPI-anchored proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GPI anchor metabolic process	1
glycolipid biosynthetic process	1
glycerophospholipid biosynthetic process	1
GPI anchored protein biosynthesis	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
primary metabolic process	1
glycosyltransferase activity	1
acetylglucosaminyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2176 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIGA	PIGH	Q14442	999
PIGA	PIGC	Q92535	999
PIGA	PIGQ	Q9BRB3	998
PIGA	PIGP	P57054	998
PIGA	PIGY	Q3MUY2	995
PIGA	PIGR	P01833	992
PIGA	DPM2	O94777	985
PIGA	CD59	P13987	972
PIGA	PIGM	Q9H3S5	934
PIGA	CD55	P08174	930
PIGA	PIGN	O95427	896
PIGA	PIGG	Q5H8A4	874
PIGA	PIGF	Q07326	849
PIGA	PIGL	Q9Y2B2	843
PIGA	PIGT	Q969N2	840

IntAct

66 interactions, top by confidence:

A	B	Type	Score
PIGA	PIGH	psi-mi:“MI:0915”(physical association)	0.740
PIGA	PIGQ	psi-mi:“MI:0915”(physical association)	0.710
PIGA	PIGP	psi-mi:“MI:0915”(physical association)	0.710
PIGA	PIGP	psi-mi:“MI:0914”(association)	0.710
PIGA	DPM2	psi-mi:“MI:0914”(association)	0.660
DPM2	PIGA	psi-mi:“MI:0914”(association)	0.660
PIGA	DPM2	psi-mi:“MI:0915”(physical association)	0.660
PIGC	PIGA	psi-mi:“MI:0914”(association)	0.640
PIGA	PIGY	psi-mi:“MI:0915”(physical association)	0.560
PIGA	PIGY	psi-mi:“MI:0914”(association)	0.560
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
VWCE	ZNF316	psi-mi:“MI:0914”(association)	0.530
EVA1C	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
PCDHB7	C2CD2L	psi-mi:“MI:0914”(association)	0.530
CCDC107	PLD2	psi-mi:“MI:0914”(association)	0.530
NAGK	ZBTB43	psi-mi:“MI:0914”(association)	0.530
THBS2	AP1G2	psi-mi:“MI:0914”(association)	0.530
PI4K2A	GABARAP	psi-mi:“MI:0914”(association)	0.530
PIGA	TRAF1	psi-mi:“MI:0915”(physical association)	0.400
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (82): PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), TRAF1 (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS), PIGA (Affinity Capture-MS)

ESM2 similar proteins: A0JN95, A4IF87, A6NJ78, B5DEQ3, B7ZMP1, D3ZLY0, E9Q4Z2, F1QDI9, G1SPE9, O14717, O15228, O22268, O55055, O95453, O95671, P37287, P69341, P97770, Q05B63, Q08J23, Q0V8R7, Q0VGM9, Q10D00, Q1HFZ0, Q2T9W2, Q4G073, Q5R5T5, Q5R962, Q5R9W8, Q5RC51, Q5RJZ1, Q6GR37, Q6H1L8, Q6NYU2, Q6YJI5, Q7TNK6, Q7YS61, Q7Z4G4, Q8JZM0, Q8R2Y8

Diamond homologs: A6ZW78, B3LKQ3, B5VSZ6, P32363, P37287, P87172, Q64323, Q94BX4, P42982, P54490, P71243, Q4H4F8, Q58459, A0A059ZV61, A0R043, A0R2E2, P26388, P71055, Q46638, Q9L1I4, H6TFZ4, P25740, Q7XNX6, Q9AET5, A2WYE9, A6LKE9, B7F7B9, O04932, O04933, O22060, P24620, P24621, P30298, P31927, P31928, P49031, P49037, Q04975, Q0JGK4, Q3S2Y2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Synthesis of glycosylphosphatidylinositol (GPI)	6	79.3×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
GPI anchor biosynthetic process	7	52.6×	2e-08
transmembrane transport	5	12.8×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

484 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	25
Uncertain significance	179
Likely benign	99
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
132815	NM_002641.4(PIGA):c.76dup (p.Tyr26fs)	Pathogenic
132816	NM_002641.4(PIGA):c.230G>T (p.Arg77Leu)	Pathogenic
132817	NM_002641.4(PIGA):c.616A>T (p.Ile206Phe)	Pathogenic
132818	NM_002641.4(PIGA):c.1030_1032del (p.Leu344del)	Pathogenic
132819	NM_002641.4(PIGA):c.278C>T (p.Pro93Leu)	Pathogenic
1676196	NM_002641.4(PIGA):c.380C>T (p.Ser127Leu)	Pathogenic
1686067	NM_002641.4(PIGA):c.350T>C (p.Phe117Ser)	Pathogenic
235496	NM_002641.4(PIGA):c.68dup (p.Ser24fs)	Pathogenic
2863441	NM_002641.4(PIGA):c.1028del (p.Asn343fs)	Pathogenic
29988	NM_002641.4(PIGA):c.1234C>T (p.Arg412Ter)	Pathogenic
4527977	NM_002641.4(PIGA):c.54_55del (p.Arg19fs)	Pathogenic
860851	NM_002641.4(PIGA):c.1354G>A (p.Asp452Asn)	Pathogenic
9957	NM_002641.4(PIGA):c.1188+2del	Pathogenic
9959	NM_002641.4(PIGA):c.459_460insA (p.His154fs)	Pathogenic
9960	NM_002641.4(PIGA):c.1115del (p.Pro372fs)	Pathogenic
9961	NM_002641.4(PIGA):c.163C>T (p.Gln55Ter)	Pathogenic
9962	NM_002641.4(PIGA):c.249_250insGT (p.Thr84fs)	Pathogenic
9963	NM_002641.4(PIGA):c.431del (p.Thr144fs)	Pathogenic
9964	NM_002641.4(PIGA):c.1323_1324del (p.Leu442fs)	Pathogenic
9965	NM_002641.4(PIGA):c.1188+1G>A	Pathogenic
9966	NM_002641.4(PIGA):c.1355_1356insAATTGAGATGGATGACTCCAGATTCTATCATTGA (p.Asp452delinsGluIleGluMetAspAspSerArgPheTyrHisTer)	Pathogenic
1029466	NM_002641.4(PIGA):c.1A>G (p.Met1Val)	Likely pathogenic
1033523	NM_002641.4(PIGA):c.986T>C (p.Val329Ala)	Likely pathogenic
1319180	NM_002641.4(PIGA):c.-63+1G>A	Likely pathogenic
1685404	NM_002641.4(PIGA):c.109A>G (p.Met37Val)	Likely pathogenic
1704280	NM_002641.4(PIGA):c.268T>C (p.Tyr90His)	Likely pathogenic
2444337	NM_002641.4(PIGA):c.1281_1282del (p.Phe428fs)	Likely pathogenic
2501811	NM_002641.4(PIGA):c.1188+1G>C	Likely pathogenic
2502420	NM_002641.4(PIGA):c.196_206del (p.Lys66fs)	Likely pathogenic
2502425	NM_002641.4(PIGA):c.151_187del (p.Ser51fs)	Likely pathogenic

SpliceAI

1038 predictions. Top by Δscore:

Variant	Effect	Δscore
X:15321770:TACCT:T	acceptor_loss	1.0000
X:15321771:ACCT:A	acceptor_loss	1.0000
X:15321773:CTGGA:C	acceptor_loss	1.0000
X:15321774:T:C	acceptor_loss	1.0000
X:15324660:CATA:C	donor_loss	1.0000
X:15324661:ATACC:A	donor_loss	1.0000
X:15324662:TACCT:T	donor_loss	1.0000
X:15324663:A:AC	donor_gain	1.0000
X:15324663:A:T	donor_loss	1.0000
X:15324664:C:CC	donor_gain	1.0000
X:15324871:CCT:C	acceptor_gain	1.0000
X:15324872:C:A	acceptor_loss	1.0000
X:15324873:T:C	acceptor_gain	1.0000
X:15325908:CAATA:C	donor_loss	1.0000
X:15325909:AATAC:A	donor_loss	1.0000
X:15325910:ATACC:A	donor_loss	1.0000
X:15325911:TAC:T	donor_loss	1.0000
X:15325912:A:AT	donor_loss	1.0000
X:15325913:C:CT	donor_loss	1.0000
X:15326044:TCC:T	acceptor_gain	1.0000
X:15326044:TCCC:T	acceptor_loss	1.0000
X:15326045:CC:C	acceptor_gain	1.0000
X:15326045:CCC:C	acceptor_gain	1.0000
X:15326046:CC:C	acceptor_gain	1.0000
X:15326047:C:CC	acceptor_gain	1.0000
X:15326048:T:C	acceptor_loss	1.0000
X:15335497:TCA:T	donor_loss	1.0000
X:15335498:CACC:C	donor_loss	1.0000
X:15335499:A:AC	donor_gain	1.0000
X:15335499:AC:A	donor_gain	1.0000

AlphaMissense

3173 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:15324694:A:G	W387R	1.000
X:15324694:A:T	W387R	1.000
X:15324863:A:C	S330R	1.000
X:15324863:A:T	S330R	1.000
X:15324865:T:G	S330R	1.000
X:15331216:C:A	G239W	1.000
X:15331218:T:A	K238I	1.000
X:15331307:A:C	N208K	1.000
X:15331307:A:T	N208K	1.000
X:15331382:A:C	C183W	1.000
X:15331383:C:T	C183Y	1.000
X:15331384:A:G	C183R	1.000
X:15331469:A:C	H154Q	1.000
X:15331469:A:T	H154Q	1.000
X:15331471:G:C	H154D	1.000
X:15324682:C:G	A391P	0.999
X:15324692:C:A	W387C	0.999
X:15324692:C:G	W387C	0.999
X:15325056:G:C	C315W	0.999
X:15325057:C:T	C315Y	0.999
X:15325058:A:G	C315R	0.999
X:15325059:G:C	F314L	0.999
X:15325059:G:T	F314L	0.999
X:15325061:A:G	F314L	0.999
X:15325066:T:A	E312V	0.999
X:15325072:A:G	L310P	0.999
X:15325075:G:A	S309F	0.999
X:15325969:C:G	G265R	0.999
X:15325969:C:T	G265R	0.999
X:15326046:C:A	G239V	0.999

dbSNP variants (sampled 300 via entrez): RS1000010392 (X:15333340 C>A,T), RS1000199420 (X:15335413 A>C), RS1000303978 (X:15321889 G>A,T), RS1000507475 (X:15337434 A>C,G), RS1001011757 (X:15328495 T>G), RS1001138170 (X:15323103 G>A,T), RS1001521830 (X:15323637 A>G), RS1001680498 (X:15330059 CG>C,CGG), RS1002015497 (X:15330969 C>T), RS1002516985 (X:15336263 T>C), RS1002576863 (X:15324302 T>A), RS1002702693 (X:15334990 C>T), RS1002778595 (X:15335773 C>T), RS1002901124 (X:15334492 A>G,T), RS1003362344 (X:15327703 TCC>T)

Disease associations

OMIM: gene MIM:311770 | disease phenotypes: MIM:300868, MIM:300818

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple congenital anomalies-hypotonia-seizures syndrome 2	Definitive	X-linked
malignant migrating partial seizures of infancy	Supportive	Autosomal dominant
infantile spasms	Supportive	Autosomal dominant
ferro-cerebro-cutaneous syndrome	Supportive	X-linked
paroxysmal nocturnal hemoglobinuria	Supportive	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	XL

Mondo (7): multiple congenital anomalies-hypotonia-seizures syndrome 2 (MONDO:0010466), paroxysmal nocturnal hemoglobinuria 1 (MONDO:0010438), intellectual disability (MONDO:0001071), paroxysmal nocturnal hemoglobinuria (MONDO:0100244), malignant migrating partial seizures of infancy (MONDO:0017385), infantile spasms (MONDO:0018097), ferro-cerebro-cutaneous syndrome (MONDO:0018346)

Orphanet (3): Multiple congenital anomalies-hypotonia-seizures syndrome type 2 (Orphanet:300496), Paroxysmal nocturnal hemoglobinuria (Orphanet:447), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

274 total (30 of 274 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000029	Testicular atrophy
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000076	Vesicoureteral reflux
HP:0000081	Duplicated collecting system
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000126	Hydronephrosis
HP:0000160	Narrow mouth
HP:0000201	Pierre-Robin sequence
HP:0000207	Triangular mouth
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000239	Large fontanelles
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000269	Prominent occiput
HP:0000271	Abnormality of the face
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000288	Abnormality of the philtrum
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000337	Broad forehead
HP:0000347	Micrognathia

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, affects expression, decreases expression	4
Valproic Acid	affects expression, decreases expression, increases expression	4
epigallocatechin gallate	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	2
Carbamazepine	increases mutagenesis, affects expression	2
Cisplatin	affects cotreatment, increases mutagenesis, decreases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	increases expression	2
Particulate Matter	decreases reaction, increases expression, increases abundance	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
trichostatin A	affects expression	1
tris(2-butoxyethyl) phosphate	increases mutagenesis	1
beta-lapachone	decreases expression, increases expression	1
cobaltous chloride	increases expression	1
zinc chromate	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
1,2-dichloroethylene	decreases reaction, increases mutagenesis	1
di-n-butylphosphoric acid	affects expression	1
2,3,3’,4,4’-pentachlorobiphenyl	decreases reaction, increases mutagenesis	1
2,3’,4,4’,5-pentachlorobiphenyl	decreases reaction, increases mutagenesis	1
chromium hexavalent ion	increases abundance, increases expression	1
CGP 52608	affects binding, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases mutagenesis, increases activity	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	increases expression, affects binding	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0KG	Ubigene HeLa PIGA KO	Cancer cell line	Female
CVCL_E0WN	Ubigene K-562 PIGA KO	Cancer cell line	Female
CVCL_E1D7	Ubigene THP-1 PIGA KO	Cancer cell line	Male
CVCL_TD48	HAP1 PIGA (-) 1	Cancer cell line	Male
CVCL_TD49	HAP1 PIGA (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

377 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01413711	PHASE4	WITHDRAWN	An Open-Label, Single and Multiple Oral Dose Pharmacokinetic Study of Vigabatrin in Infants With Infantile Spasms
NCT02092883	PHASE4	COMPLETED	Evaluation of Neuroinflammation in Children With Infantile Spasms
NCT03866681	PHASE4	UNKNOWN	Sirolimus Combined With Low-dose Warfarin for the Treatment of Refractory PNH
NCT04320602	PHASE4	COMPLETED	Ravulizumab in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Currently Treated With High-Dose Eculizumab
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01575639	PHASE3	COMPLETED	Prednisolone in Infantile Spasms- High Dose Versus Usual Dose
NCT01828437	PHASE3	COMPLETED	Addition of Pyridoxine to Prednisolone in Infantile Spasms
NCT02299115	PHASE3	WITHDRAWN	Prednisolone Versus Vigabatrin in the First-line Treatment of Infantile Spasms
NCT02953548	PHASE3	COMPLETED	Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms (GWPCARE7)
NCT02954887	PHASE3	COMPLETED	Phase 3 Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms: Open-label Extension Phase (GWPCARE7)
NCT02946463	PHASE3	COMPLETED	ALXN1210 (Ravulizumab) Versus Eculizumab in Complement Inhibitor Treatment-Naïve Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)
NCT03056040	PHASE3	COMPLETED	ALXN1210 Versus Eculizumab in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
NCT03406507	PHASE3	COMPLETED	A Study of Ravulizumab (ALXN1210) in Children and Adolescents With Paroxysmal Nocturnal Hemoglobinuria
NCT03500549	PHASE3	COMPLETED	Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
NCT03531255	PHASE3	ACTIVE_NOT_RECRUITING	Pegcetacoplan Long Term Safety and Efficacy Extension Study
NCT03588026	PHASE3	COMPLETED	Treating Paroxysmal Nocturnal Haemoglobinuria Patients With rVA576
NCT03748823	PHASE3	COMPLETED	Ravulizumab Subcutaneous (SC) Versus Ravulizumab Intravenous (IV) in Adults With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
NCT03818607	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants With PNH
NCT03829449	PHASE3	TERMINATED	rVA576 (Coversin) Long Term Safety and Efficacy Surveillance Study
NCT04058158	PHASE3	COMPLETED	A Study to Compare SB12 (Proposed Eculizumab Biosimilar) to Soliris in Subjects With Paroxysmal Nocturnal Haemoglobinuria
NCT04060264	PHASE3	COMPLETED	Clinical Trial of BCD-148 and Soliris® for the Treatment of Patients With Paroxysmal Nocturnal Hemoglobinuria
NCT04085601	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients With PNH
NCT04162470	PHASE3	TERMINATED	REGN3918 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) to Evaluate Its Long Term Safety, Efficacy and Tolerability.
NCT04432584	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Safety, Pharmacokinetics, and Efficacy of Crovalimab Versus Eculizumab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Complement Inhibitors
NCT04434092	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors
NCT04463056	PHASE3	COMPLETED	Efficacy and Safety of Elizaria® vs. Soliris® in Patients With PNH
NCT04469465	PHASE3	COMPLETED	Danicopan as Add-on Therapy to a C5 Inhibitor in Paroxysmal Nocturnal Hemoglobinuria (PNH) Participants Who Have Clinically Evident Extravascular Hemolysis (EVH)(ALPHA)
NCT04558918	PHASE3	COMPLETED	Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment
NCT04654468	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition
NCT04679103	PHASE3	COMPLETED	A Safety and Immunogenicity Study in Long-term Treatment of Eculizumab (JSC GENERIUM, Russian Federation)
NCT04747613	PHASE3	ACTIVE_NOT_RECRUITING	Long-term Safety and Tolerability of Iptacopan in Patients With Paroxysmal Nocturnal Hemoglobinuria
NCT04820530	PHASE3	COMPLETED	Study of Efficacy and Safety of Twice Daily Oral Iptacopan (LNP023) in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy
NCT05131204	PHASE3	TERMINATED	Efficacy and Safety of the Combination of Pozelimab and Cemdisiran Versus Continued Eculizumab or Ravulizumab Treatment in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria
NCT05133531	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate How Safe Pozelimab + Cemdisiran Combination Therapy is and How Well it Works in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have Not Recently Received or Have Not Received Complement Inhibitor Treatment
NCT05389449	PHASE3	ACTIVE_NOT_RECRUITING	A Long-term Safety and Efficacy Study of Danicopan as an Add-on Therapy to Complement Component 5 Inhibitor (C5i) in Participants With PNH
NCT05630001	PHASE3	COMPLETED	Single Arm, Open Label Trial With Iptacopan Treatment for 24 Weeks, in Patients on Stable Regimen of Anti-C5 Who Switch to Iptacopan.
NCT05744921	PHASE3	RECRUITING	A Study in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) to Evaluate How Safe Long-term Treatment With Pozelimab + Cemdisiran Combination Therapy is and How Well it Works