PIGN

Chr 18AR

phosphatidylinositol glycan anchor biosynthesis class N

Also known as: GPI-ETI, MCAHS, MCAHS1, MCD4, MDC4, PIG-N

NCBI Gene: 23556ENSG00000197563UniProt: O95427

This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Multiple congenital anomalies-hypotonia-seizures syndrome 1MIM #614080
AR
574
ClinVar variants
99
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PIGN
🧬
Gene-Disease Validity (ClinGen)
multiple congenital anomalies-hypotonia-seizures syndrome 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
99 Pathogenic / Likely Pathogenic· 156 VUS of 574 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.
1.02LOEUF
pLI 0.000
Z-score 1.41
OE 0.78 (0.60–1.02)
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.
0.42Z-score
OE missense 0.94 (0.87–1.02)
412 obs / 436.4 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.0.78 (0.60–1.02)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.87–1.02)
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.1.04
0≤1.21.6
LoF obs/exp: 38 / 48.6Missense obs/exp: 412 / 436.4Syn Z: -0.35

ClinVar Variant Classifications

574 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60
Likely Pathogenic39
VUS156
Likely Benign279
Benign39
Conflicting1
60
Pathogenic
39
Likely Pathogenic
156
VUS
279
Likely Benign
39
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
20
1
39
0
60
Likely Pathogenic
25
2
12
0
39
VUS
0
135
17
4
156
Likely Benign
0
1
168
110
279
Benign
0
0
39
0
39
Conflicting
—1
Total45139275114574

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

View in ClinVar →

Protein Context — Lollipop Plot

PIGN · protein map & ClinVar variants

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

Gene2Phenotype Curations

PIGN-related multiple congenital anomalies-hypotonia-seizures syndrome

definitive
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. DisordersEye
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Multiple congenital anomalies-hypotonia-seizures syndrome 1

MIM #614080

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PIGN
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Post-infectious glomerulonephritis.
Balasubramanian R et al.·Paediatr Int Child Health
2017Review
Clinico-Pathogenic Similarities and Differences between Infection-Related Glomerulonephritis and C3 Glomerulopathy.
Wada Y et al.·Int J Mol Sci
2023Review
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.
Conte F et al.·Int J Mol Sci
2023Review
Postinfectious glomerulonephritis.
Kambham N·Adv Anat Pathol
2012Review
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
Loong L et al.·Genet Med
2023
PIGN encephalopathy: Characterizing the epileptology.
Bayat A et al.·Epilepsia
2022
A Meta-Analysis and Cohort Study of Histopathologic and Clinical Outcomes in ANCA-Negative versus -Positive Vasculitis.
Floyd L et al.·Kidney360
2023Meta-analysis
PIGN-Related Disease in Two Lithuanian Families: A Report of Two Novel Pathogenic Variants, Molecular and Clinical Characterisation.
Siavrienė E et al.·Medicina (Kaunas)
2022
Vertical nystagmus as a feature of PIGN-related glycosylphosphatidylinositol biosynthesis defects.
Jezela-Stanek A et al.·Clin Neurol Neurosurg
2020Review
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