PIGA

Chr XXLR

phosphatidylinositol glycan anchor biosynthesis class A

Also known as: GPI3, MCAHS2, NEDEPH, PIG-A, PNH1

NCBI Gene: 5277 ENSG00000165195 UniProt: P37287 OMIM: 311770

The protein is essential for the first step of GPI anchor biosynthesis, catalyzing the synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI), which is required for anchoring proteins to cell surfaces. Germline mutations cause X-linked recessive multiple congenital anomalies-hypotonia-seizures syndrome and neurodevelopmental disorder with epilepsy and hemochromatosis, while somatic mutations lead to the acquired hematologic condition paroxysmal nocturnal hemoglobinuria. Disease predominantly results from loss-of-function mutations disrupting GPI anchor synthesis.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI), the first intermediate in the biosynthetic pathway of GPI anchor. The GPI anchor is a glycolipid found on many blood cells and which serves to anchor proteins to the cell surface. Paroxysmal nocturnal hemoglobinuria, an acquired hematologic disorder, has been shown to result from mutations in this gene. Alternate splice variants have been characterized. A related pseudogene is located on chromosome 12. [provided by RefSeq, Jun 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Multiple congenital anomalies-hypotonia-seizures syndrome 2MIM #300868

XLR

Neurodevelopmental disorder with epilepsy and hemochromatosisMIM #301072

XLR

Paroxysmal nocturnal hemoglobinuria, somaticMIM #300818

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · complex neurodevelopmental disorder · XL · ClinGen 2024
Definitive · multiple congenital anomalies-hypotonia-seizures syndrome 2 · XL · G2P
Supportive · malignant migrating partial seizures of infancy · AD · Orphanet
Supportive · ferro-cerebro-cutaneous syndrome · XL · Orphanet

+1 more curated pair

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.30LOEUF

pLI 0.961

Z-score 2.95

OE 0.00 (0.00–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.17Z-score

OE missense 0.56 (0.47–0.65)

105 obs / 188.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.30)

0≤0.351.4

Missense OE?0.56 (0.47–0.65)

0≤0.61.4

Synonymous OE?0.75

0≤1.21.6

LoF obs/exp: 0 / 10.1Missense obs/exp: 105 / 188.9Syn Z: 1.61

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

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 450

261 rare PASS variants

Rare truncating (LoF)

1 in 2,000

15 rare PASS variants

Rare synonymous (reference)

1 in 410

134 rare PASS variants

Rare missense and truncating variants are carried at similar rates in PIGA; this gene does not show strong loss-of-function constraint by this measure. 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)	~561k	1 in 580	1 in 2,000
South Asian	~36k	1 in 400	none seen
Remaining (unassigned)	~31k	1 in 500	1 in 1,400
European (Finnish)	~27k	1 in 970	≈ 1 in 27,000
Admixed American	~23k	1 in 400	≈ 1 in 5,600
African / African American	~21k	1 in 410	≈ 1 in 18,000
East Asian	~20k	1 in 200	1 in 2,400
Ashkenazi Jewish	~13k	1 in 1,800	≈ 1 in 13,000
Middle Eastern	~2,758	1 in 270	none seen

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.