PIGS

protein-coding

phosphatidylinositol glycan anchor biosynthesis class S, the group of Glycosylphosphatidylinositol transamidase complex|Phosphatidylinositol glycan anchor biosynthesis

Gene summary

This gene encodes a protein that is involved in GPI-anchor biosynthesis. The glycosylphosphatidylinositol (GPI) anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. [provided by RefSeq, Jul 2008]

MANE transcript

NM_033198.4

Inheritance

ClinVar variants

P:16U:97B:35

Top phenotype

Developmental and epileptic encephalopathy 95

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr17:28,553,383-28,571,794

External References & Databases

Ensembl (ENSG00000087111)

Transcript & Mutation Effects

hg38 • Region Span ~18.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycosylphosphatidylinositol biosynthesis defect 18DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0029140

Submitter: ClinGen

*PIGS* was first reported in relation to autosomal recessive developmental and epileptic encephalopathy 95 (MONDO:0029140) in 2018 (Nguyen TTM et al., PMID:30269814). This condition is caused by variants in the *PIGS* gene, which encodes an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. [provided by RefSeq, Jul 2008]. 87 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar; 13 of these variants are classified as pathogenic or likely pathogenic in ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Eleven variants that have been reported in 9 probands in 3 publications (Nguyen TTM et al., 2018, PMID:30269814; Efthymiou S et al., 2021, PMID:33410539; Zhang L et al., 2020, PMID:32612635), are included in this curation. This gene-disease relationship is also supported by the protein interactions of the protein; *PIGS*, with GPI8, GAA1, and *PIG‑T *to form a stable, multi-component enzyme complex essential for the biochemical process of GPI anchoring. (Ohishi K et al., 2001, PMID:11483512). In summary, there is definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Disorder of Glycosylation GCEP on the meeting date May 21, 2025 (SOP Version 11).

glycosylphosphatidylinositol biosynthesis defect 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029140

Submitter: G2P

glycosylphosphatidylinositol biosynthesis defect 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029140

Submitter: Labcorp Genetics (formerly Invitae)

glycosylphosphatidylinositol biosynthesis defect 18MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0029140

Submitter: Ambry Genetics

glycosylphosphatidylinositol biosynthesis defect 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029140

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 95AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic

Intervention: Neurologic

Rationale: Among other manifestations, individuals may have difficult-to-control seizures, and management with oral pyridoxine has been described as beneficial

Refs: 30269814; 33410539

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGS variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 76

not providedTotal: 50

not specifiedTotal: 29

Glycosylphosphatidylinositol biosynthesis defect 18Total: 20

PIGS-related disorderTotal: 18

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033198.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	22 clinvar		23
missense	3 clinvar	2 clinvar	93 clinvar	10 clinvar	3 clinvar	111
nonsense	1 clinvar	3 clinvar	2 clinvar			6
start loss						0
frameshift	1 clinvar	3 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar				3
Total	6	10	97	32	3	148

Highest pathogenic variant AF is 0.00002395308

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033198.4	RefSeq	NP_149975.1	12	MANE Select
ENST00000308360.8	Ensembl	ENSP00000309430.7	12	MANE Select
ENST00000268758.13	Ensembl	ENSP00000268758.9	2	Standard
ENST00000395346.6	Ensembl	ENSP00000378755.2	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosylphosphatidylinositol (GPI)-anchor biosynthesis - Homo sapiens (human)
Attachment of GPI anchor to uPAR
Post-translational modification: synthesis of GPI-anchored proteins
Post-translational protein modification
Metabolism of proteins

Biological Process

attachment of GPI anchor to protein

Molecular Function

GPI-anchor transamidase activity
protein binding

Cellular Component

endoplasmic reticulum membrane
membrane
GPI-anchor transamidase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000308360
Coding exons: 12
Length: 18490
Individuals with no LoFs: 125693
Homozygous LoFs: 0
Heterozygous LoFs: 55
Defined: 125748
p: 0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.780	285	325	0.878	0.0000178	3564
Missense (PolyPhen)		65	91.769	0.7083		1036
Synonymous	0.172	133	136	0.981	0.00000762	1172
Loss of Function	2.45	12	25.3	0.475	0.00000116	303

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00014	0.00012	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00028	0.00027	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00028	0.00028	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the GPI transamidase complex. Essential for transfer of GPI to proteins, particularly for formation of carbonyl intermediates. {ECO:0000269|PubMed:11483512}.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.708
RVIS EVS: 0.09
RVIS percentile EVS: 60.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.421

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium