PIGY

Chr 4AR

phosphatidylinositol glycan anchor biosynthesis class Y

Also known as: HPMRS6, PIG-Y

NCBI Gene: 84992ENSG00000255072UniProt: Q3MUY2

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]

Primary Disease Associations & Inheritance

Hyperphosphatasia with impaired intellectual development syndrome 6MIM #616809
AR
46
ClinVar variants
27
Pathogenic / LP
0.10
pLI score
0
Active trials
Clinical Summary— PIGY
🧬
Gene-Disease Validity (ClinGen)
hyperphosphatasia with intellectual disability syndrome 6 · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.10) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
27 Pathogenic / Likely Pathogenic· 12 VUS of 46 total submissions

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.
1.88LOEUF
pLI 0.097
Z-score 0.11
OE 0.89 (0.25–1.88)
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.
-0.32Z-score
OE missense 1.15 (0.90–1.49)
41 obs / 35.6 exp
Tolerant

Tolerant to missense variation

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.0.89 (0.25–1.88)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.15 (0.90–1.49)
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.0.83
0≤1.21.6
LoF obs/exp: 1 / 1.1Missense obs/exp: 41 / 35.6Syn Z: 0.52

ClinVar Variant Classifications

46 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic1
VUS12
Likely Benign4
Benign3
26
Pathogenic
1
Likely Pathogenic
12
VUS
4
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
24
0
26
Likely Pathogenic
0
0
1
0
1
VUS
0
12
0
0
12
Likely Benign
0
2
0
2
4
Benign
0
0
2
1
3
Total11527346

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

View in ClinVar →

Protein Context — Lollipop Plot

PIGY · protein map & ClinVar variants

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

Gene2Phenotype Curations

PIGY-related glycosylphosphatidylinositol deficiency

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
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 6

MIM #616809

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Defining mitochondrial protein functions through deep multiomic profiling.
Rensvold JW et al.·Nature
2022
Expanding the phenotype of PIGP deficiency to multiple congenital anomalies-hypotonia-seizures syndrome.
Martín-Grau C et al.·Clin Genet
2023
Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies.
Ilkovski B et al.·Hum Mol Genet
2015Case report
Diagnosis and etiology of congenital muscular dystrophy: We are halfway there.
O'Grady GL et al.·Ann Neurol
2016
Silencing of genes required for glycosylphosphatidylinositol anchor biosynthesis in Burkitt lymphoma.
Hu R et al.·Exp Hematol
2009
Mutations in the PIGW gene associated with hyperphosphatasia and mental retardation syndrome: a case report.
Fu L et al.·BMC Pediatr
2019Case report
Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders.
Thompson MD et al.·Genes (Basel)
2024Cohort
Multisystem disorders, severe developmental delay and seizures in two affected siblings, expanding the phenotype of PIGC deficiency.
Pons L et al.·Eur J Med Genet
2020Case report
A post glycosylphosphatidylinositol (GPI) attachment to proteins, type 2 (PGAP2) variant identified in Mabry syndrome index cases: Molecular genetics of the prototypical inherited GPI disorder.
Thompson MD et al.·Eur J Med Genet
2020Case 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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools