PIGN

Chr 18AR

phosphatidylinositol glycan anchor biosynthesis class N

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

NCBI Gene: 23556 ENSG00000197563 UniProt: O95427 OMIM: 606097

The protein transfers phosphoethanolamine to the first mannose of the GPI anchor during GPI-anchor biosynthesis in the endoplasmic reticulum, which is essential for anchoring proteins to cell surfaces. Autosomal recessive mutations cause multiple congenital anomalies-hypotonia-seizures syndrome 1. The pathogenic mechanism involves defective GPI anchor synthesis, which disrupts normal protein anchoring to cell membranes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Multiple congenital anomalies-hypotonia-seizures syndrome 1MIM #614080

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · multiple congenital anomalies-hypotonia-seizures syndrome 1 · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.02

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — PIGN

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.42Z-score

OE missense 0.94 (0.87–1.02)

412 obs / 436.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.78 (0.60–1.02)

0≤0.351.4

Missense OE?0.94 (0.87–1.02)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 38 / 48.6Missense obs/exp: 412 / 436.4Syn Z: -0.35

Background carrier burden — how many people carry a rare variant somewhere in PIGN?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 62

1,236 rare PASS variants

Rare truncating (LoF)

1 in 380

267 rare PASS variants

Rare synonymous (reference)

1 in 100

422 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PIGN. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 71	1 in 390
South Asian	~43k	1 in 46	1 in 260
Remaining (unassigned)	~30k	1 in 43	1 in 240
European (Finnish)	~27k	1 in 140	1 in 1,400
Admixed American	~22k	1 in 46	1 in 640
African / African American	~21k	1 in 56	1 in 530
East Asian	~20k	1 in 60	1 in 190
Ashkenazi Jewish	~13k	1 in 280	1 in 1,400
Middle Eastern	~2,884	1 in 64	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 28 coding exons well covered in gnomAD exomes; exon 11 poorly covered; exons 6, 7, 8, 10, 12 and 15 more marginal. Genomes: all 28.? see exons ↓