PIGV

protein-coding

phosphatidylinositol glycan anchor biosynthesis class V, the group of Dolichyl D-mannosyl phosphate dependent mannosyltransferases|Phosphatidylinositol glycan anchor biosynthesis

Gene summary

This gene encodes a mannosyltransferase enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is a complex glycolipid that functions as a membrane anchor for many proteins and plays a role in multiple cellular processes including protein sorting and signal transduction. The encoded protein is localized to the endoplasmic reticulum and transfers the second mannose to the GPI backbone. Mutations in this gene are associated with hyperphosphatasia cognitive disability syndrome. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Feb 2011]

MANE transcript

NM_017837.4

Inheritance

ClinVar variants

P:20U:195B:140

Top phenotype

Hyperphosphatasia with impaired intellectual development syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr1:26,787,054-26,800,659

External References & Databases

Ensembl (ENSG00000060642)

Transcript & Mutation Effects

hg38 • Region Span ~13.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperphosphatasia with impaired intellectual development syndrome 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009398

Submitter: Ambry Genetics

hyperphosphatasia with impaired intellectual development syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009398

Submitter: G2P

hyperphosphatasia-intellectual disability syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016596

Submitter: Orphanet

hyperphosphatasia with impaired intellectual development syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009398

Submitter: PanelApp Australia

hyperphosphatasia with impaired intellectual development syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009398

Submitter: Labcorp Genetics (formerly Invitae)

hyperphosphatasia with impaired intellectual development syndrome 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009398

Submitter: ClinGen

*PIGV* was first reported in relation to autosomal recessive hyperphosphatasia with intellectual disability syndrome 1 in 2010 (Krawitz et al., PMID: 20802478). 14 unique variants (13 missense, 1 nonsense) that have been reported in 18 probands in 8 publications (PMIDs: 20802478, 21739589, 22315194, 24129430, 27177984, 28688840, 28817240, 37863628) are included in this curation. One recurrent variant in the European population (NM_017837.4:c.1022C>A, p.Ala341Glu) has been observed in the homozygous state in 5 probands and in the compound heterozygous state in 9 probands. The mechanism of pathogenicity appears to be loss of function, although most variants reported in conjunction with this condition are missense variants without functional studies. This gene-disease relationship is also supported by a mouse knock-in model and a Chinese hamster ovary cell knockout model (PMIDs: 33402532, 22228761). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date June 18, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Hyperphosphatasia with impaired intellectual development syndrome 1AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Gastrointestinal; 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: 5465362; 1724113; 16638507; 17351347; 20080219; 20802478; 20578257; 21739589; 22315194

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIGV variants in ClinVar

7 Conditions Cataloged

not providedTotal: 305

Inborn genetic diseasesTotal: 76

Hyperphosphatasia with intellectual disability syndrome 1Total: 51

not specifiedTotal: 39

PIGV-related disorderTotal: 16

Hyperphosphatasia-intellectual disability syndromeTotal: 1

Elevated circulating alkaline phosphatase concentrationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017837.4. 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			3 clinvar	127 clinvar		130
missense	3 clinvar	9 clinvar	176 clinvar	13 clinvar		201
nonsense		5 clinvar	5 clinvar			10
start loss						0
frameshift		2 clinvar	11 clinvar			13
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	3	17	195	140	0	355

Highest pathogenic variant AF is 0.00012452883

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017837.4	RefSeq	NP_060307.2	3	MANE Select
ENST00000674202.1	Ensembl	ENSP00000501479.1	3	MANE Select
NM_001202554.2	RefSeq	NP_001189483.1	3	Standard
NM_001374478.1	RefSeq	NP_001361407.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosylphosphatidylinositol (GPI)-anchor biosynthesis - Homo sapiens (human)
Vitamin B6-dependent and responsive disorders
Synthesis of glycosylphosphatidylinositol (GPI)
Post-translational modification: synthesis of GPI-anchored proteins
Post-translational protein modification

Biological Process

GPI anchor biosynthetic process
preassembly of GPI anchor in ER membrane
mannosylation

Molecular Function

mannosyltransferase activity
glycolipid mannosyltransferase activity
dolichyl-phosphate-mannose-glycolipid alpha-mannosyltransferase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane
mannosyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374145
Coding exons: 3
Length: 10927
Individuals with no LoFs: 125690
Homozygous LoFs: 0
Heterozygous LoFs: 58
Defined: 125748
p: 0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.398	240	258	0.930	0.0000139	3169
Missense (PolyPhen)		78	93.661	0.83279		1231
Synonymous	0.202	106	109	0.975	0.00000582	1074
Loss of Function	0.811	14	17.7	0.792	9.52e-7	190

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00034	0.00034	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Alpha-1,6-mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the second mannose to the glycosylphosphatidylinositol during GPI precursor assembly. {ECO:0000269|PubMed:15623507, ECO:0000269|PubMed:15720390}.;
Disease: DISEASE: Hyperphosphatasia with mental retardation syndrome 1 (HPMRS1) [MIM:239300]: A severe syndrome characterized by elevated serum alkaline phosphatase, severe mental retardation, seizures, hypotonia, facial dysmorphism, and hypoplastic terminal phalanges. {ECO:0000269|PubMed:20802478}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.258
RVIS EVS: -0.4
RVIS percentile EVS: 26.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.465

Gene Damage Prediction

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