PIGN

Summary

PIGN (phosphatidylinositol glycan anchor biosynthesis class N, HGNC:8967) is a protein-coding gene on chromosome 18q21.33, encoding GPI ethanolamine phosphate transferase 1 (O95427). Ethanolamine phosphate transferase that catalyzes an ethanolamine phosphate (EtNP) transfer from phosphatidylethanolamine (PE) to the 2-OH position of the first alpha-1,4-linked mannose of a 2-acyl-6-[alpha-D-mannosyl-(1->6)-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-rad….

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.

Source: NCBI Gene 23556 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple congenital anomalies-hypotonia-seizures syndrome 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,367 total — 107 pathogenic, 64 likely-pathogenic
• Phenotypes (HPO): 146
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_176787

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8967
Approved symbol	PIGN
Name	phosphatidylinositol glycan anchor biosynthesis class N
Location	18q21.33
Locus type	gene with protein product
Status	Approved
Aliases	MCD4, PIG-N
Ensembl gene	ENSG00000197563
Ensembl biotype	protein_coding
OMIM	606097
Entrez	23556

Gene structure

Transcript identifiers

Ensembl transcripts: 78 — 59 protein_coding, 9 nonsense_mediated_decay, 6 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000357637, ENST00000400334, ENST00000585344, ENST00000585458, ENST00000585923, ENST00000585926, ENST00000586566, ENST00000587134, ENST00000587942, ENST00000588571, ENST00000588748, ENST00000589339, ENST00000589414, ENST00000589720, ENST00000590765, ENST00000590948, ENST00000591238, ENST00000592803, ENST00000593225, ENST00000638167, ENST00000638183, ENST00000638329, ENST00000638369, ENST00000638424, ENST00000638435, ENST00000638591, ENST00000638858, ENST00000638904, ENST00000638936, ENST00000638977, ENST00000639174, ENST00000639214, ENST00000639342, ENST00000639372, ENST00000639491, ENST00000639600, ENST00000639681, ENST00000639758, ENST00000639902, ENST00000639912, ENST00000640050, ENST00000640145, ENST00000640170, ENST00000640248, ENST00000640252, ENST00000640268, ENST00000640540, ENST00000640593, ENST00000640682, ENST00000640704, ENST00000640876, ENST00000858611, ENST00000858612, ENST00000858613, ENST00000858614, ENST00000858615, ENST00000858616, ENST00000858617, ENST00000858618, ENST00000858619, ENST00000858620, ENST00000858621, ENST00000858622, ENST00000858623, ENST00000927326, ENST00000927327, ENST00000927328, ENST00000962939, ENST00000962940, ENST00000962941, ENST00000962942, ENST00000962943, ENST00000962944, ENST00000962945, ENST00000962946, ENST00000962947, ENST00000962948, ENST00000962949

RefSeq mRNA: 2 — MANE Select: NM_176787 NM_012327, NM_176787

CCDS: CCDS45879

Canonical transcript exons

ENST00000640252 — 31 exons

Exon	Start	End
ENSE00001011789	62148214	62148338
ENSE00001011791	62154545	62154651
ENSE00001011795	62157129	62157227
ENSE00001104709	62113134	62113316
ENSE00001104719	62082673	62082746
ENSE00001104721	62114561	62114639
ENSE00001143135	62138983	62139075
ENSE00001230592	62138243	62138298
ENSE00001230801	62109834	62109973
ENSE00001294631	62161133	62161385
ENSE00001362588	62162253	62162329
ENSE00001417241	62186844	62187056
ENSE00003464376	62085209	62085264
ENSE00003482293	62145909	62146025
ENSE00003488582	62140420	62140479
ENSE00003514139	62095848	62095950
ENSE00003527513	62088756	62088842
ENSE00003548987	62090476	62090578
ENSE00003553113	62072673	62072725
ENSE00003553211	62074779	62074821
ENSE00003569767	62106789	62106881
ENSE00003575098	62102794	62102902
ENSE00003603434	62105543	62105634
ENSE00003605196	62084531	62084606
ENSE00003613355	62101075	62101183
ENSE00003617161	62106986	62107085
ENSE00003626402	62143306	62143346
ENSE00003627608	62163531	62163656
ENSE00003675271	62157687	62157808
ENSE00003679388	62146971	62147101
ENSE00003802431	62041164	62045979

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 96.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2821 / max 199.4382, expressed in 1781 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172238	11.4827	1775
172237	0.7994	465

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.30	gold quality
calcaneal tendon	UBERON:0003701	93.59	gold quality
lower esophagus mucosa	UBERON:0035834	90.52	gold quality
colonic epithelium	UBERON:0000397	90.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.06	gold quality
islet of Langerhans	UBERON:0000006	87.39	gold quality
tendon	UBERON:0000043	87.28	gold quality
adrenal tissue	UBERON:0018303	86.99	gold quality
rectum	UBERON:0001052	86.57	gold quality
esophagus mucosa	UBERON:0002469	86.55	gold quality
esophagus squamous epithelium	UBERON:0006920	85.41	gold quality
choroid plexus epithelium	UBERON:0003911	84.26	gold quality
ventricular zone	UBERON:0003053	84.01	gold quality
epithelium of esophagus	UBERON:0001976	83.91	gold quality
pancreas	UBERON:0001264	83.60	gold quality
skin of abdomen	UBERON:0001416	83.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.43	gold quality
bone marrow cell	CL:0002092	83.18	gold quality
body of pancreas	UBERON:0001150	82.80	gold quality
skin of leg	UBERON:0001511	82.73	gold quality
monocyte	CL:0000576	82.60	gold quality
gall bladder	UBERON:0002110	82.58	gold quality
vagina	UBERON:0000996	82.52	gold quality
stomach	UBERON:0000945	82.33	gold quality
minor salivary gland	UBERON:0001830	82.27	gold quality
body of stomach	UBERON:0001161	82.21	gold quality
mouth mucosa	UBERON:0003729	81.84	gold quality
mononuclear cell	CL:0000842	81.81	gold quality
squamous epithelium	UBERON:0006914	81.73	gold quality
leukocyte	CL:0000738	81.67	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-150728	yes	3733.34
E-CURD-79	yes	2133.71
E-MTAB-8205	yes	2007.13
E-GEOD-134144	yes	1724.99
E-MTAB-8142	yes	36.70
E-MTAB-7249	yes	10.93
E-ANND-3	yes	7.28
E-CURD-135	no	6806.30
E-MTAB-7381	no	2326.84
E-MTAB-7316	no	1545.06
E-HCAD-6	no	889.06
E-GEOD-137537	no	16.89
E-MTAB-9801	no	3.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

108 targeting PIGN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548AR-3P	99.85	71.26	3889

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 14)

• Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. (PMID:21493957)
• PIGN encodes phosphatidylinositol-glycan biosynthesis class N protein. (PMID:22876578)
• Findings confirm that developmental delay, hypotonia, and epilepsy combined with congenital anomalies are common phenotypes of PIGN mutations and add progressive cerebellar atrophy to this clinical spectrum. (PMID:24253414)
• The mutated PIGN caused a significant decrease of the overall glycosylphoshatidylinositol-anchored proteins and CD24 expression which is sufficient to cause severe phenotypic expression. (PMID:26364997)
• PIGN mutation is associated with multiple congenital anomalies hypotonia seizures syndrome related epilepsy. (PMID:26394714)
• Study reports compound heterozygous mutations in PIGN in two siblings with Fryns syndrome, and a homozygous mutation in an unrelated affected individual. However, two further individuals with Fryns syndrome did not carry mutations in this gene, suggesting genetic heterogeneity in this syndrome. (PMID:27038415)
• PIGN-1/PIGN is required for quality control in Caenorhabditis elegans and in mammalian cells. (PMID:27980068)
• PIGN is a novel biomarker of CIN and leukemic transformation/progression in a subgroup of patients with MDS or AML-MRC. (PMID:28187452)
• Disease associated mutation L311W reduces enzymatic activity rather than affecting protein levels. (PMID:28327575)
• Loss of function PIGN alleles causes Fryns syndrome. Founder effect for PIGN intragenic deletion is observed in La Reunion and other Indian Ocean islands. (PMID:29330547)
• Novel insights into the clinico-radiological spectrum of phenotypes associated to PIGN mutations. (PMID:34051595)
• PIGN spatiotemporally regulates the spindle assembly checkpoint proteins in leukemia transformation and progression. (PMID:34561473)
• Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study. (PMID:36322149)
• PIGN-Related Disease in Two Lithuanian Families: A Report of Two Novel Pathogenic Variants, Molecular and Clinical Characterisation. (PMID:36363484)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	pign	ENSDARG00000077532
mus_musculus	Pign	ENSMUSG00000056536
rattus_norvegicus	Pign	ENSRNOG00000014866
drosophila_melanogaster	PIG-N	FBGN0033479
drosophila_melanogaster	CG6790	FBGN0037915
drosophila_melanogaster	CG5342	FBGN0037916
drosophila_melanogaster	CG4907	FBGN0039010
drosophila_melanogaster	CG13978	FBGN0039518
caenorhabditis_elegans	pign-1	WBGENE00021840

Protein

Protein identifiers

GPI ethanolamine phosphate transferase 1 — O95427 (reviewed: O95427)

Alternative names: GPI-ethanolamine transferase I, MCD4 homolog, Phosphatidylinositol-glycan biosynthesis class N protein

All UniProt accessions (27): A0A1W2PNH8, A0A1W2PNQ8, A0A1W2PNR0, A0A1W2PNW5, A0A1W2PPA0, A0A1W2PPB6, A0A1W2PPK6, A0A1W2PPR7, A0A1W2PQ49, A0A1W2PQA9, A0A1W2PQP4, A0A1W2PQR8, A0A1W2PQZ1, A0A1W2PR74, A0A1W2PRH3, A0A1W2PS19, O95427, K7EID9, K7EJM6, K7EL34, K7ELE1, K7EMD7, K7ENK2, K7EPJ2, K7EQG0, K7ERX5, K7ESH9

UniProt curated annotations — full annotation on UniProt →

Function. Ethanolamine phosphate transferase that catalyzes an ethanolamine phosphate (EtNP) transfer from phosphatidylethanolamine (PE) to the 2-OH position of the first alpha-1,4-linked mannose of a 2-acyl-6-[alpha-D-mannosyl-(1->6)-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol (also termed H3) intermediate to generate a 2-acyl-6-[alpha-D-mannosyl-(1->6)-2-phosphoethanolamine-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol and participates in the eighth step of the glycosylphosphatidylinositol-anchor biosynthesis. Also transfers the EtNP on a mannosyl GPI intermediate, 2-acyl-6-(alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl)-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol (also termed H2). May act as suppressor of replication stress and chromosome missegregation.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) [MIM:614080] An autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor biosynthesis.

Similarity. Belongs to the PIGG/PIGN/PIGO family. PIGN subfamily.

RefSeq proteins (2): NP_036459, NP_789744* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002591	Phosphodiest/P_Trfase	Family
IPR007070	GPI_EtnP_transferase_1	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR017852	GPI_EtnP_transferase_1_C	Domain
IPR037671	PIGN_N	Domain

Pfam: PF01663, PF04987

Catalyzed reactions (Rhea), 2 shown:

• a 2-acyl-6-(alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl)-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine = a 2-acyl-6-[2-phosphoethanolamine-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol + a 1,2-diacyl-sn-glycerol (RHEA:60896)
• a 2-acyl-6-[alpha-D-mannosyl-(1->6)-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine = a 2-acyl-6-[alpha-D-mannosyl-(1->6)-2-phosphoethanolamine-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol + a 1,2-diacyl-sn-glycerol (RHEA:83767)

UniProt features (42 total): topological domain 16, transmembrane region 15, sequence variant 7, glycosylation site 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95427-F1	88.33	0.62

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (3): 128, 192, 350

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-162710	Synthesis of glycosylphosphatidylinositol (GPI)

MSigDB gene sets: 494 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, REACTOME_SYNTHESIS_OF_GLYCOSYLPHOSPHATIDYLINOSITOL_GPI, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_PROTEIN_MATURATION

GO Biological Process (1): GPI anchor biosynthetic process (GO:0006506)

GO Molecular Function (2): mannose-ethanolamine phosphotransferase activity (GO:0051377), transferase activity (GO:0016740)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational modification: synthesis of GPI-anchored proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
GPI anchor metabolic process	1
glycolipid biosynthetic process	1
glycerophospholipid biosynthetic process	1
GPI anchored protein biosynthesis	1
phosphotransferase activity, for other substituted phosphate groups	1
catalytic activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

878 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIGN	LEMD3	Q9Y2U8	957
PIGN	PIGA	P37287	896
PIGN	PIGW	Q7Z7B1	774
PIGN	PIGL	Q9Y2B2	771
PIGN	PIGK	Q92643	767
PIGN	PIGB	Q92521	746
PIGN	PIGH	Q14442	735
PIGN	PIGM	Q9H3S5	735
PIGN	PIGV	Q9NUD9	733
PIGN	PIGT	Q969N2	727
PIGN	PIGC	Q92535	724
PIGN	PGAP2	Q9UHJ9	713
PIGN	PIGQ	Q9BRB3	708
PIGN	PIGZ	Q86VD9	693
PIGN	PIGY	Q3MUY2	646

IntAct

60 interactions, top by confidence:

A	B	Type	Score
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3B1	psi-mi:“MI:0914”(association)	0.530
SPPL2B	UQCRQ	psi-mi:“MI:0914”(association)	0.530
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
FJX1	PIGN	psi-mi:“MI:0915”(physical association)	0.370
YIPF3	TMEM223	psi-mi:“MI:0914”(association)	0.350
TXNDC15	ORC4	psi-mi:“MI:0914”(association)	0.350
VIPR2	C15orf61	psi-mi:“MI:0914”(association)	0.350
ATP2B2	GPR89A	psi-mi:“MI:0914”(association)	0.350
FPR2	GPR89A	psi-mi:“MI:0914”(association)	0.350
PTGIR	GPAA1	psi-mi:“MI:0914”(association)	0.350
TUBB4B	TUBA1B	psi-mi:“MI:0914”(association)	0.350
ATP2B2	ESYT2	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
AVPR2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
RNF149	CCDC85C	psi-mi:“MI:0914”(association)	0.350
SCN4A	C2CD4B	psi-mi:“MI:0914”(association)	0.350
RXFP1	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
VIPR2	RABGAP1L	psi-mi:“MI:0914”(association)	0.350
PIGN	GPR89A	psi-mi:“MI:0914”(association)	0.350
OPALIN	GPR89A	psi-mi:“MI:0914”(association)	0.350

BioGRID (90): PIGN (Affinity Capture-RNA), PIGN (Affinity Capture-RNA), PIGN (Affinity Capture-RNA), PIGN (Affinity Capture-MS), PIGN (Synthetic Growth Defect), PIGN (Affinity Capture-MS), PIGN (Affinity Capture-MS), PIGN (Affinity Capture-MS), PIGN (Affinity Capture-MS), PIGN (Affinity Capture-MS), PIGN (Affinity Capture-MS), PIGN (Affinity Capture-MS), PIGN (Affinity Capture-MS), PIGN (Affinity Capture-MS), PIGN (Proximity Label-MS)

ESM2 similar proteins: A0JNC1, A0PK00, A1L2R7, A2BIE7, A3KNK1, A6QPF8, A7XZ53, A8DZH4, D3ZEH5, O35052, O95427, P98191, Q05B45, Q0VFK3, Q17QL9, Q1LY80, Q28CY9, Q3TA38, Q5BL21, Q5EAX9, Q5EAY8, Q5FWV6, Q5HZE2, Q5RET6, Q5U239, Q5ZMP3, Q63ZG0, Q68EY2, Q6DD44, Q6DE21, Q6ZMG9, Q7ZUA6, Q8BXA5, Q8C172, Q8C1E7, Q8CIF6, Q8NBJ9, Q8WVP7, Q91XU8, Q92903

Diamond homologs: O95427, P36051, Q2H0X9, Q2U0S9, Q2U9J2, Q4ILH3, Q4W9R7, Q5A3M6, Q5AXD1, Q6BWE3, Q6C0Z3, Q6CW36, Q6FJ81, Q757X5, Q7SAP1, Q8WZK2, Q9R1S3, O13663, P40367, Q07830, Q09782, Q4WDM5, Q5H8A4, Q6BZ57, Q6C7Q6, Q6CLN2, Q6FPB2, Q74ZS2, Q758B8, Q8TEQ8, Q8TGB2, Q9JJI6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-activating G protein-coupled receptor signaling pathway	7	11.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1367 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	107
Likely pathogenic	64
Uncertain significance	437
Likely benign	568
Benign	94

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
101047	NM_176787.5(PIGN):c.808T>C (p.Ser270Pro)	Pathogenic
1027678	NM_176787.5(PIGN):c.1660G>A (p.Gly554Arg)	Pathogenic
1071330	NM_176787.5(PIGN):c.2423dup (p.Asn808fs)	Pathogenic
1073972	NC_000018.9:g.(?59763071)(59763193_?)del	Pathogenic
1073974	NC_000018.9:g.(?59805466)(59806318_?)del	Pathogenic
1073975	NC_000018.9:g.(?59768298)(59770145_?)del	Pathogenic
1358099	NM_176787.5(PIGN):c.439A>T (p.Lys147Ter)	Pathogenic
1361618	NM_176787.5(PIGN):c.347G>A (p.Trp116Ter)	Pathogenic
1364069	NM_176787.5(PIGN):c.2147C>G (p.Ser716Ter)	Pathogenic
1378427	NM_176787.5(PIGN):c.2026_2027del (p.Arg676fs)	Pathogenic
1439160	NM_176787.5(PIGN):c.1665_1668dup (p.Val557Ter)	Pathogenic
1452539	NM_176787.5(PIGN):c.221+1dup	Pathogenic
1453175	NM_176787.5(PIGN):c.2251_2252del (p.Leu751fs)	Pathogenic
1686068	NM_176787.5(PIGN):c.1517G>A (p.Trp506Ter)	Pathogenic
1686069	NM_176787.5(PIGN):c.491_492del (p.Glu164fs)	Pathogenic
1703504	NM_176787.5(PIGN):c.1859+3A>G	Pathogenic
2019913	NM_176787.5(PIGN):c.2482G>T (p.Gly828Ter)	Pathogenic
2048119	NM_176787.5(PIGN):c.531G>A (p.Trp177Ter)	Pathogenic
2084420	NM_176787.5(PIGN):c.1767+1del	Pathogenic
2095415	NM_176787.5(PIGN):c.24del (p.Leu9fs)	Pathogenic
2427546	NC_000018.9:g.(?59713069)(59828606_?)del	Pathogenic
2427547	NC_000018.9:g.(?59805456)(59806328_?)del	Pathogenic
264634	NM_176787.5(PIGN):c.755A>T (p.Asp252Val)	Pathogenic
264635	NM_176787.5(PIGN):c.2340T>A (p.Tyr780Ter)	Pathogenic
264638	NM_176787.5(PIGN):c.324_549+196del	Pathogenic
264639	NM_176787.5(PIGN):c.1966C>T (p.Gln656Ter)	Pathogenic
264640	NM_176787.5(PIGN):c.1674+1G>C	Pathogenic
264641	NM_176787.5(PIGN):c.694A>T (p.Lys232Ter)	Pathogenic
2695830	NM_176787.5(PIGN):c.1614del (p.Tyr539fs)	Pathogenic
2697730	NM_176787.5(PIGN):c.1924_1928del (p.Arg641_Lys642insTer)	Pathogenic

SpliceAI

5367 predictions. Top by Δscore:

Variant	Effect	Δscore
18:62088656:AACAC:A	donor_gain	1.0000
18:62088657:A:C	donor_gain	1.0000
18:62095844:ATAC:A	donor_gain	1.0000
18:62105542:CA:C	donor_gain	1.0000
18:62105562:TTCG:T	donor_gain	1.0000
18:62106783:TCATA:T	donor_loss	1.0000
18:62106784:CATA:C	donor_loss	1.0000
18:62106785:ATACC:A	donor_loss	1.0000
18:62106786:TA:T	donor_loss	1.0000
18:62106787:A:C	donor_loss	1.0000
18:62106788:CCTT:C	donor_loss	1.0000
18:62106880:ACC:A	acceptor_loss	1.0000
18:62106896:C:CT	acceptor_gain	1.0000
18:62106897:A:T	acceptor_gain	1.0000
18:62106984:A:AC	donor_gain	1.0000
18:62106985:C:CC	donor_gain	1.0000
18:62138307:CAAG:C	acceptor_gain	1.0000
18:62138308:A:T	acceptor_gain	1.0000
18:62138978:TTTAC:T	donor_loss	1.0000
18:62138979:TTACC:T	donor_loss	1.0000
18:62138980:TACC:T	donor_loss	1.0000
18:62138981:A:AT	donor_loss	1.0000
18:62138982:C:CG	donor_loss	1.0000
18:62146026:C:CC	acceptor_gain	1.0000
18:62146027:T:C	acceptor_loss	1.0000
18:62146967:TAA:T	donor_loss	1.0000
18:62146969:A:AC	donor_gain	1.0000
18:62146969:A:C	donor_loss	1.0000
18:62146969:AC:A	donor_gain	1.0000
18:62146969:ACC:A	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002181 (18:62060922 T>C), RS1000004880 (18:62105889 T>C), RS1000036739 (18:62060679 G>A), RS1000042312 (18:62117784 T>C), RS1000050701 (18:62047675 G>C), RS1000052621 (18:62149132 T>G), RS1000087565 (18:62017542 G>A), RS1000170153 (18:62047688 C>G), RS1000178646 (18:62058366 C>T), RS1000191948 (18:62186282 C>T), RS1000207600 (18:62154441 T>C), RS1000212720 (18:62057992 G>A), RS1000280050 (18:62098530 T>C,G), RS1000282515 (18:62055011 C>A,G,T), RS1000304897 (18:62018353 T>C)

Disease associations

OMIM: gene MIM:606097 | disease phenotypes: MIM:614080, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple congenital anomalies-hypotonia-seizures syndrome 1	Definitive	Autosomal recessive
Fryns syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
multiple congenital anomalies-hypotonia-seizures syndrome 1	Definitive	AR

Mondo (4): multiple congenital anomalies-hypotonia-seizures syndrome 1 (MONDO:0013563), schizophrenia (MONDO:0005090), multiple congenital anomalies-hypotonia-seizures syndrome (MONDO:0100247), Fryns syndrome (MONDO:0009253)

Orphanet (2): Multiple congenital anomalies-hypotonia-seizures syndrome (Orphanet:280633), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

146 total (30 of 146 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000047	Hypospadias
HP:0000072	Hydroureter
HP:0000073	Ureteral duplication
HP:0000076	Vesicoureteral reflux
HP:0000110	Renal dysplasia
HP:0000126	Hydronephrosis
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000256	Macrocephaly
HP:0000269	Prominent occiput
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_1255	Metabolite levels	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004761	uric acid measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538070	Fryns syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
periodate-oxidized adenosine	affects expression	1
methacrylaldehyde	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
abrine	decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
Vehicle Emissions	increases abundance, increases expression	1
Formaldehyde	decreases expression	1
Ozone	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
Quercetin	decreases expression	1
Thiram	decreases expression	1
Vanadates	decreases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1
Particulate Matter	increases abundance, increases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression, increases oxidation	1

Cellosaurus cell lines

2 cell lines: 1 finite cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2VE	GM26113	Finite cell line	Male
CVCL_F0ZK	GM29523	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

302 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety