PIGY

protein-coding

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

Gene summary

The protein encoded by this gene is part of the GPI-N-acetylglucosaminyltransferase (GIP-GnT) complex which initiates the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is synthesized in the endoplasmic reticulum and serves as an anchor for many surface proteins. Proteins containing GPI anchors can have an important role in cell-cell interactions. The transcript for this gene is bicistronic. The downstream open reading frame encodes this GPI-GnT complex protein, while the upstream open reading frame encodes a protein with unknown function, as represented by GeneID:100996939. [provided by RefSeq, Aug 2012]

MANE transcript

NM_001042616.3

Inheritance

ClinVar variants

P:1U:10B:5

Top phenotype

Hyperphosphatasia with impaired intellectual development syndrome 6

gnomAD constraint

pLI —, LoF o/e 0.89

Max pathogenic AF

—

Genomic locus

chr4:88,520,998-88,523,776

External References & Databases

Ensembl (ENSG00000255072)

Transcript & Mutation Effects

hg38 • Region Span ~2.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperphosphatasia with impaired intellectual development syndrome 6MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014780

Submitter: PanelApp Australia

hyperphosphatasia with impaired intellectual development syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014780

Submitter: G2P

hyperphosphatasia with impaired intellectual development syndrome 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014780

Submitter: ClinGen

*PIGY* was first reported in relation to autosomal recessive Hyperphosphatasia with impaired intellectual development syndrome 6 (MONDO:0014780) in 2015 (Ilkovski B et al., 2015, PMID: 26293662). This condition is caused by variants in the *PIGY* gene, which encodes the smallest subunit of GPI-GnT, which is directly associated with the catalytic subunit *PIG-A*.(PMID:16162815) 45 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar; 27 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. Two variants that have been reported in 2 probands in 1 publication (Ilkovski B et al., 2015, PMID: 26293662), are included in this curation. This gene-disease relationship is also supported by protein interaction; *PIGY* directly interacts with *PIG‑A *through co‑immunoprecipitation (co‑IP) and GST pull‑down experiments. In these assays, when *PIG‑A* (the catalytic subunit) is pulled down, *PIG‑Y* is co‑precipitated, indicating a physical binding between the two proteins. (Murakami Y et al., 2005, PMID: 16162815. 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 Disorder of Glycosylation GCEP on the meeting date October 20, 2025 (SOP Version 11).

hyperphosphatasia with impaired intellectual development syndrome 6LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014780

Submitter: Labcorp Genetics (formerly Invitae)

hyperphosphatasia with impaired intellectual development syndrome 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014780

Submitter: Ambry Genetics

hyperphosphatasia-intellectual disability syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016596

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hyperphosphatasia with impaired intellectual development syndrome 6AR

Manifestation: Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic

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: 26293662

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGY variants in ClinVar

3 Conditions Cataloged

not providedTotal: 13

Hyperphosphatasia with intellectual disability syndrome 6Total: 3

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001042616.3. 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				3 clinvar		3
missense	1 clinvar		9 clinvar	2 clinvar		12
nonsense						0
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	10	5	0	16

Highest pathogenic variant AF is 6.8414334e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001042616.3	RefSeq	NP_001036081.1	1	MANE Select
ENST00000527353.2	Ensembl	ENSP00000432688.1	1	MANE Select
ENST00001140644.1	Ensembl	ENSP00000813756.1	1	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

GPI anchor biosynthetic process
preassembly of GPI anchor in ER membrane

Molecular Function

phosphatidylinositol N-acetylglucosaminyltransferase activity

Cellular Component

glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex
endoplasmic reticulum membrane
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000527353
Coding exons: 1
Length: 217
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.321	41	35.6	1.15	0.00000159	454
Missense (PolyPhen)		5	4.8866	1.0232		76
Synonymous	0.518	12	14.5	0.827	7.15e-7	151
Loss of Function	0.106	1	1.12	0.892	4.59e-8	18

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the GPI-GlcNAc transferase (GPI-GnT) complex in the endoplasmic reticulum, a complex that catalyzes transfer of GlcNAc from UDP-GlcNAc to an acceptor phosphatidylinositol, the first step in the production of GPI- anchors for cell surface proteins. May act by regulating the catalytic subunit PIGA. {ECO:0000269|PubMed:16162815}.;
Disease: DISEASE: Hyperphosphatasia with mental retardation syndrome 6 (HPMRS6) [MIM:616809]: An autosomal recessive, multisystem disorder characterized by severe developmental delay, dysmorphism, seizures, cataracts, and early death in some patients. {ECO:0000269|PubMed:26293662}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: 0.19
RVIS percentile EVS: 66.57

Essentials

Essential (CRISPR): N
Indispensability pred.: N
Indispensability score: 0.169

Gene Damage Prediction

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