PIGH

protein-coding

phosphatidylinositol glycan anchor biosynthesis class H, the group of Phosphatidylinositol glycan anchor biosynthesis|Glycosylphosphatidylinositol-N-acetylglucosaminyltransferase complex

Gene summary

This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI anchor is a glycolipid found on many blood cells and which serves to anchor proteins to the cell surface. The protein encoded by this gene is a subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004569.5

Inheritance

ClinVar variants

P:3U:28B:5

Top phenotype

Glycosylphosphatidylinositol biosynthesis defect 17

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr14:67,581,955-67,600,286

External References & Databases

Ensembl (ENSG00000100564)

Transcript & Mutation Effects

hg38 • Region Span ~18.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycosylphosphatidylinositol biosynthesis defect 17LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060724

Submitter: ClinGen

PIGH was first reported in relation to autosomal recessive glycosylphosphatidylinositol biosynthesis defect 17 in 2018 (Pagnamenta et al., PMID:29573052 and Nguyen et al. PMID:29603516). Three variants (initiation codon, missense) that have been reported in 6 probands in 4 publications (PMIDs 29573052, 29603516, 33156547, 35445667) are included in this curation. Patients have a range of symptoms, including seizures, hypotonia, autism, intellectual disability, and motor deficits. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is also supported by in vitro and in vivo assays showing a deficiency in glycosylphosphatidylinositol (GPI) biosynthesis (PMIDs 29603516, 9463366). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on October 2nd, 2025 (SOP Version 11).

glycosylphosphatidylinositol biosynthesis defect 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060724

Submitter: PanelApp Australia

glycosylphosphatidylinositol biosynthesis defect 17LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060724

Submitter: Ambry Genetics

glycosylphosphatidylinositol biosynthesis defect 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060724

Submitter: Labcorp Genetics (formerly Invitae)

glycosylphosphatidylinositol biosynthesis defect 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060724

Submitter: G2P

Clinical Genomic Database (CGD)

Glycosylphosphatidylinositol biosynthesis defect 17AR

Manifestation: Biochemical; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 29573052; 29603516; 33156547; 35445667

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGH variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 27

PIGH-related disorderTotal: 7

not providedTotal: 4

Glycosylphosphatidylinositol biosynthesis defect 17Total: 3

not specifiedTotal: 2

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004569.5. 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				2 clinvar	2 clinvar	4
missense		2 clinvar	28 clinvar	1 clinvar		31
nonsense						0
start loss	1 clinvar					1
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	2	28	3	2	36

Highest pathogenic variant AF is 0.000034087938

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004569.5	RefSeq	NP_004560.1	4	MANE Select
ENST00000216452.9	Ensembl	ENSP00000216452.4	4	MANE Select
NM_001363694.2	RefSeq	NP_001350623.1	4	Standard
NM_001440640.1	RefSeq	NP_001427569.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

cellular protein modification process
GPI anchor biosynthetic process
preassembly of GPI anchor in ER membrane

Molecular Function

catalytic activity
phosphatidylinositol N-acetylglucosaminyltransferase activity

Cellular Component

glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex
endoplasmic reticulum
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216452
Coding exons: 4
Length: 18333
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125731
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.948	69	95.0	0.726	0.00000441	1200
Missense (PolyPhen)		20	25.009	0.79972		317
Synonymous	1.73	25	38.7	0.646	0.00000179	376
Loss of Function	1.81	2	7.26	0.276	3.07e-7	97

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00012	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000081	0.000079	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Part of the complex catalyzing the transfer of N- acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol, the first step of GPI biosynthesis.;

Recessive Scores

pRec: 0.125

Intolerance Scores

LoFtool: 0.392
RVIS EVS: -0.23
RVIS percentile EVS: 36.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.571

Gene Damage Prediction

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