PIGV

Chr 1AR

phosphatidylinositol glycan anchor biosynthesis class V

Also known as: GPI-MT-II, HPMRS1, PIG-V

NCBI Gene: 55650ENSG00000060642UniProt: Q9NUD9

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]

Primary Disease Associations & Inheritance

Hyperphosphatasia with impaired intellectual development syndrome 1MIM #239300
AR
398
ClinVar variants
13
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— PIGV
🧬
Gene-Disease Validity (ClinGen)
hyperphosphatasia with intellectual disability syndrome 1 · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 215 VUS of 398 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.24LOEUF
pLI 0.000
Z-score 0.81
OE 0.79 (0.52–1.24)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.40Z-score
OE missense 0.93 (0.84–1.03)
240 obs / 258.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.79 (0.52–1.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.84–1.03)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 14 / 17.7Missense obs/exp: 240 / 258.0Syn Z: 0.20

ClinVar Variant Classifications

398 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic6
VUS215
Likely Benign138
Benign7
Conflicting25
7
Pathogenic
6
Likely Pathogenic
215
VUS
138
Likely Benign
7
Benign
25
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
4
0
7
Likely Pathogenic
1
5
0
0
6
VUS
10
170
32
3
215
Likely Benign
0
4
16
118
138
Benign
0
0
7
0
7
Conflicting
—25
Total1118259121398

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PIGV · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PIGV-related hyperphosphatasia with intellectual developmental disorder

definitive
ARLoss Of FunctionAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hyperphosphatasia with impaired intellectual development syndrome 1

MIM #239300

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.
Conte F et al.·Int J Mol Sci
2023Review
Characteristics of Neuroimaging and Behavioural Phenotype in Polish Patients with PIGV-CDG-An Observational Study and Literature Review.
Hutny M et al.·Genes (Basel)
2023Review
Alternative splicing in ovarian cancer.
Wei L et al.·Cell Commun Signal
2024Review
Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome.
Horn D et al.·Eur J Hum Genet
2014
Hyperphosphatasia-mental retardation syndrome due to PIGV mutations: expanded clinical spectrum.
Horn D et al.·Am J Med Genet A
2011Case report
Phenotypic variability in hyperphosphatasia with seizures and neurologic deficit (Mabry syndrome).
Thompson MD et al.·Am J Med Genet A
2012
Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up.
Stockler S et al.·Mol Genet Metab
2011Review
Prenatal ultrasound findings associated with PIGW variants: One more piece in the FRYNS syndrome puzzle? PIGW-related prenatal findings.
Ronzoni L et al.·Prenat Diagn
2022Review
Whole exome-based variant profiling and functional network characterization in neural tube defects.
Akcali N et al.·Childs Nerv Syst
2025Functional
Clinical and genetic analysis of two Chinese infants with Mabry syndrome.
Xue J et al.·Brain Dev
2016Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet

External Resources

Links to major genomics databases and tools