PIGO

Summary

PIGO (phosphatidylinositol glycan anchor biosynthesis class O, HGNC:23215) is a protein-coding gene on chromosome 9p13.3, encoding GPI ethanolamine phosphate transferase 3, catalytic subunit (Q8TEQ8). Catalytic subunit of the ethanolamine phosphate transferase 3 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the third alpha-1,2-linked mannose of the a 2-acyl-6-[alpha-D-mannosyl-(1->2)-alpha-D-mannosyl-(1->6….

This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid which contains three mannose molecules in its core backbone. The GPI-anchor is found on many blood cells and serves to anchor proteins to the cell surface. This protein is involved in the transfer of ethanolaminephosphate (EtNP) to the third mannose in GPI. At least three alternatively spliced transcripts encoding two distinct isoforms have been found for this gene.

Source: NCBI Gene 84720 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,067 total — 55 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 82
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_032634

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23215
Approved symbol	PIGO
Name	phosphatidylinositol glycan anchor biosynthesis class O
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434M222, FLJ00135, PIG-O
Ensembl gene	ENSG00000165282
Ensembl biotype	protein_coding
OMIM	614730
Entrez	84720

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 19 protein_coding, 6 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000298004, ENST00000361778, ENST00000378617, ENST00000465745, ENST00000472208, ENST00000474436, ENST00000491687, ENST00000492770, ENST00000700254, ENST00000700255, ENST00000700256, ENST00000700257, ENST00000700258, ENST00000700259, ENST00000700260, ENST00000700261, ENST00000700262, ENST00000700263, ENST00000700264, ENST00000907113, ENST00000907114, ENST00000907115, ENST00000907116, ENST00000907117, ENST00000929241, ENST00000929242, ENST00000929243, ENST00000929244, ENST00000929245, ENST00000929246, ENST00000949398, ENST00000949399

RefSeq mRNA: 3 — MANE Select: NM_032634 NM_001201484, NM_032634, NM_152850

CCDS: CCDS6575, CCDS6576

Canonical transcript exons

ENST00000378617 — 11 exons

Exon	Start	End
ENSE00001091865	35093030	35093209
ENSE00001091867	35093421	35093580
ENSE00001091876	35090066	35090280
ENSE00003525110	35094216	35094359
ENSE00003574786	35090466	35090672
ENSE00003660519	35089380	35089450
ENSE00003680449	35093901	35094024
ENSE00003690300	35095055	35095566
ENSE00003979342	35096155	35096591
ENSE00003979344	35091240	35092767
ENSE00003979346	35088688	35089221

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 90.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.1868 / max 57.4897, expressed in 1796 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100564	12.1868	1796

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	90.07	gold quality
diaphragm	UBERON:0001103	89.85	silver quality
vena cava	UBERON:0004087	88.78	silver quality
islet of Langerhans	UBERON:0000006	88.70	gold quality
right lobe of thyroid gland	UBERON:0001119	88.65	gold quality
left lobe of thyroid gland	UBERON:0001120	87.77	gold quality
type B pancreatic cell	CL:0000169	87.76	silver quality
right uterine tube	UBERON:0001302	87.47	gold quality
metanephros cortex	UBERON:0010533	87.18	gold quality
thyroid gland	UBERON:0002046	87.02	gold quality
cervix squamous epithelium	UBERON:0006922	86.78	silver quality
body of pancreas	UBERON:0001150	86.76	gold quality
pancreas	UBERON:0001264	86.45	gold quality
right adrenal gland	UBERON:0001233	86.40	gold quality
olfactory bulb	UBERON:0002264	86.37	silver quality
right adrenal gland cortex	UBERON:0035827	86.19	gold quality
right lobe of liver	UBERON:0001114	85.83	gold quality
left adrenal gland	UBERON:0001234	85.77	gold quality
body of stomach	UBERON:0001161	85.76	gold quality
left adrenal gland cortex	UBERON:0035825	85.69	gold quality
body of tongue	UBERON:0011876	85.64	silver quality
adrenal cortex	UBERON:0001235	85.41	gold quality
granulocyte	CL:0000094	85.38	gold quality
subthalamic nucleus	UBERON:0001906	85.02	gold quality
adenohypophysis	UBERON:0002196	84.85	gold quality
left ovary	UBERON:0002119	84.64	gold quality
adrenal gland	UBERON:0002369	84.61	gold quality
minor salivary gland	UBERON:0001830	84.59	gold quality
pharyngeal mucosa	UBERON:0000355	84.53	gold quality
mucosa of urinary bladder	UBERON:0001259	84.50	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting PIGO, 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-656-3P	100.00	72.15	2788
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-4433A-3P	97.75	62.82	1435
HSA-MIR-4712-5P	97.24	67.79	775
HSA-MIR-770-5P	97.24	68.10	758
HSA-MIR-4436B-5P	96.71	68.37	1346
HSA-MIR-431-5P	96.16	66.50	652

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 4)

• Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS. (PMID:22683086)
• Novel PIGO mutations expand the clinical spectrum of PIGO abnormalities to include epileptic encephalopathy with mild elevation of alkaline phosphatase (ALP). (PMID:24417746)
• Disease associated PIGO missense mutations resulted in decreased activity in vitro. (PMID:28327575)
• PIGO deficiency shows variable phenotypes from infantile lethality to mild learning difficulties (PMID:28337824)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pigo	ENSDARG00000011743
mus_musculus	Pigo	ENSMUSG00000028454
rattus_norvegicus	Pigo	ENSRNOG00000009930
drosophila_melanogaster	PIG-O	FBGN0034346
caenorhabditis_elegans	pigo-1	WBGENE00016159

Protein

Protein identifiers

GPI ethanolamine phosphate transferase 3, catalytic subunit — Q8TEQ8 (reviewed: Q8TEQ8)

Alternative names: Phosphatidylinositol-glycan biosynthesis class O protein

All UniProt accessions (7): A0A8V8TPI0, A0A8V8TPI4, A0A8V8TPZ0, A0A8V8TQ25, A0A8V8TQT1, A0A8V8TR33, Q8TEQ8

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the ethanolamine phosphate transferase 3 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the third alpha-1,2-linked mannose of the a 2-acyl-6-[alpha-D-mannosyl-(1->2)-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 (also termed H6) intermediate to generate a a 2-acyl-6-[6-phosphoethanolamine-alpha-D-mannosyl-(1->2)-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 (also termed H7) and participates in the tenth step of the glycosylphosphatidylinositol-anchor biosynthesis.

Subunit / interactions. Part of the ethanolamine phosphate transferase 3 complex composed by PIGO and PIGF. PIGF is required to stabilize PIGO.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Hyperphosphatasia with impaired intellectual development syndrome 2 (HPMRS2) [MIM:614749] An autosomal recessive form of intellectual disability characterized by facial dysmorphism, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures. 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. PIGO subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TEQ8-1	1	yes
Q8TEQ8-2	2

RefSeq proteins (3): NP_001188413, NP_116023, NP_690577 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002591	Phosphodiest/P_Trfase	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR037675	PIG-O_N	Domain
IPR039524	PIGO/GPI13	Family

Pfam: PF01663

Catalyzed reactions (Rhea), 1 shown:

• a 2-acyl-6-[alpha-D-mannosyl-(1->2)-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-glycero-3-phosphoethanolamine = a 2-acyl-6-[6-phosphoethanolamine-alpha-D-mannosyl-(1->2)-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:61012)

UniProt features (33 total): transmembrane region 14, sequence variant 10, sequence conflict 6, chain 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEQ8-F1	82.57	0.47

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 (1): 268

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 308 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, REACTOME_SYNTHESIS_OF_GLYCOSYLPHOSPHATIDYLINOSITOL_GPI, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, AP2_Q3, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_PROTEIN_MATURATION, MODULE_379

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

GO Molecular Function (4): mannose-ethanolamine phosphotransferase activity (GO:0051377), transferase activity (GO:0016740), transferase activity, transferring phosphorus-containing groups (GO:0016772), phosphotransferase activity, for other substituted phosphate groups (GO:0016780)

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), 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
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
transferase activity	1
transferase activity, transferring phosphorus-containing groups	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1118 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIGO	PIGV	Q9NUD9	914
PIGO	PIGL	Q9Y2B2	876
PIGO	PGAP2	Q9UHJ9	855
PIGO	PIGM	Q9H3S5	845
PIGO	PIGT	Q969N2	841
PIGO	PIGW	Q7Z7B1	837
PIGO	PIGA	P37287	811
PIGO	PIGK	Q92643	807
PIGO	PIGB	Q92521	796
PIGO	PIGH	Q14442	794
PIGO	PIGC	Q92535	774
PIGO	PIGY	Q3MUY2	774
PIGO	PIGQ	Q9BRB3	764
PIGO	GPAA1	O43292	762
PIGO	PIGP	P57054	758

IntAct

73 interactions, top by confidence:

A	B	Type	Score
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
	UBXN8	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC30A2	RER1	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
KCNA2	FADS1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
KCNA2	TMEM129	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
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
ZDHHC12	NBAS	psi-mi:“MI:0914”(association)	0.350
SIDT2	KLRG2	psi-mi:“MI:0914”(association)	0.350
PSCA	METTL15	psi-mi:“MI:0914”(association)	0.350
SCN4A	C2CD4B	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
NKAIN1	GPR89A	psi-mi:“MI:0914”(association)	0.350
ATP2A3	GPR89A	psi-mi:“MI:0914”(association)	0.350

BioGRID (111): PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), POTEI (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), PIGO (Affinity Capture-MS), PIGO (Affinity Capture-MS)

ESM2 similar proteins: A3KN25, A4IFL1, O18968, O70491, O75712, O95377, P08033, P25305, P28230, P28231, P28232, P28233, P28234, P28235, P29414, P33725, P35212, P36380, P36382, P41987, Q01231, Q02738, Q02739, Q03190, Q08DF2, Q0V8E7, Q0VCR2, Q29RK8, Q4QR83, Q58D78, Q5E9Z5, Q5R7B4, Q60HF7, Q64448, Q6WGK6, Q7M734, Q80VM9, Q866T7, Q8BSD4, Q8CE93

Diamond homologs: O13663, P40367, Q07830, Q09782, Q2U9J2, Q4WDM5, Q5H8A4, Q6BZ57, Q6C7Q6, Q6CLN2, Q6FPB2, Q74ZS2, Q758B8, Q8TEQ8, Q8TGB2, Q9JJI6, O95427, Q9R1S3, Q4W9R7, Q5AXD1

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PIGG	“up-regulates quantity by stabilization”	PIGO	binding
PIGF	“down-regulates quantity by destabilization”	PIGO

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
R-HSA-425366	5	14.6×	3e-03
SLC-mediated transmembrane transport	7	6.7×	6e-03
Transport of small molecules	11	4.5×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
sodium ion transport	5	15.3×	2e-03
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	14.8×	1e-03
monoatomic ion transmembrane transport	6	14.0×	1e-03
positive regulation of cytosolic calcium ion concentration	7	9.2×	2e-03
adenylate cyclase-activating G protein-coupled receptor signaling pathway	6	7.6×	1e-02
cell surface receptor signaling pathway	9	6.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1067 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	14
Uncertain significance	547
Likely benign	357
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068540	NM_032634.4(PIGO):c.2257del (p.Ser753fs)	Pathogenic
1070437	NM_032634.4(PIGO):c.1445_1449del (p.Leu482fs)	Pathogenic
1070693	NM_032634.4(PIGO):c.773del (p.Val258fs)	Pathogenic
1072029	NM_032634.4(PIGO):c.2602_2605del (p.Leu868fs)	Pathogenic
1076728	NM_032634.4(PIGO):c.2360_2363del (p.Pro787fs)	Pathogenic
1299276	NM_032634.4(PIGO):c.2069_2082del (p.Arg690fs)	Pathogenic
1392155	NM_032634.4(PIGO):c.1329G>A (p.Trp443Ter)	Pathogenic
1451783	NM_032634.4(PIGO):c.1942del (p.Cys648fs)	Pathogenic
1454378	NM_032634.4(PIGO):c.1222C>T (p.Gln408Ter)	Pathogenic
1457267	NM_032634.4(PIGO):c.1087C>T (p.Gln363Ter)	Pathogenic
1903867	NM_032634.4(PIGO):c.894_895del (p.Phe299fs)	Pathogenic
1909826	NM_032634.4(PIGO):c.36G>A (p.Trp12Ter)	Pathogenic
1945917	NM_032634.4(PIGO):c.1126C>T (p.Arg376Ter)	Pathogenic
1956756	NM_032634.4(PIGO):c.1361dup (p.Thr455fs)	Pathogenic
2017642	NM_032634.4(PIGO):c.309del (p.Lys103fs)	Pathogenic
2034143	NM_032634.4(PIGO):c.2413C>T (p.Gln805Ter)	Pathogenic
2106509	NM_032634.4(PIGO):c.1923C>A (p.Cys641Ter)	Pathogenic
2120565	NM_032634.4(PIGO):c.2953A>T (p.Arg985Ter)	Pathogenic
2146203	NM_032634.4(PIGO):c.1114C>T (p.Gln372Ter)	Pathogenic
2415324	NM_032634.4(PIGO):c.28del (p.Leu10fs)	Pathogenic
2710215	NM_032634.4(PIGO):c.2217del (p.Ser740fs)	Pathogenic
2717350	NM_032634.4(PIGO):c.2442_2457del (p.Arg814fs)	Pathogenic
2732848	NM_032634.4(PIGO):c.3067C>T (p.Gln1023Ter)	Pathogenic
2734011	NM_032634.4(PIGO):c.2368C>T (p.Gln790Ter)	Pathogenic
2754191	NM_032634.4(PIGO):c.2117G>A (p.Trp706Ter)	Pathogenic
2763210	NM_032634.4(PIGO):c.1184del (p.Gln395fs)	Pathogenic
2786782	NM_032634.4(PIGO):c.1189C>T (p.Gln397Ter)	Pathogenic
2815586	NM_032634.4(PIGO):c.985del (p.Leu329fs)	Pathogenic
2839158	NM_032634.4(PIGO):c.1361del (p.Gly454fs)	Pathogenic
2839262	NM_032634.4(PIGO):c.327_336del (p.Ile110fs)	Pathogenic

SpliceAI

2068 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35089396:T:A	donor_gain	1.0000
9:35092586:C:CA	donor_gain	1.0000
9:35092636:AGCCC:A	donor_gain	1.0000
9:35093026:CTA:C	donor_loss	1.0000
9:35093028:A:T	donor_loss	1.0000
9:35093029:C:CA	donor_loss	1.0000
9:35093029:CCTG:C	donor_gain	1.0000
9:35093124:T:TA	donor_gain	1.0000
9:35093125:C:A	donor_gain	1.0000
9:35093209:CCTA:C	acceptor_loss	1.0000
9:35093210:C:CC	acceptor_gain	1.0000
9:35093210:CT:C	acceptor_loss	1.0000
9:35093211:T:C	acceptor_loss	1.0000
9:35093899:A:AC	donor_gain	1.0000
9:35093900:C:CC	donor_gain	1.0000
9:35094021:TCCA:T	acceptor_gain	1.0000
9:35094022:CCA:C	acceptor_gain	1.0000
9:35094022:CCAC:C	acceptor_gain	1.0000
9:35094023:CA:C	acceptor_gain	1.0000
9:35094023:CAC:C	acceptor_gain	1.0000
9:35094025:C:CC	acceptor_gain	1.0000
9:35094210:GCTCA:G	donor_loss	1.0000
9:35094211:CTCAC:C	donor_loss	1.0000
9:35094212:TCA:T	donor_loss	1.0000
9:35094213:CA:C	donor_loss	1.0000
9:35094214:A:AC	donor_gain	1.0000
9:35094215:C:CA	donor_gain	1.0000
9:35094215:CT:C	donor_gain	1.0000
9:35094215:CTG:C	donor_gain	1.0000
9:35094215:CTGG:C	donor_gain	1.0000

AlphaMissense

6974 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35093976:T:A	D235V	0.995
9:35094327:A:G	W182R	0.995
9:35094327:A:T	W182R	0.995
9:35093976:T:G	D235A	0.994
9:35095482:G:C	F28L	0.994
9:35095482:G:T	F28L	0.994
9:35095484:A:G	F28L	0.994
9:35089388:A:C	F1044L	0.993
9:35089388:A:T	F1044L	0.993
9:35089390:A:G	F1044L	0.993
9:35092549:G:C	F446L	0.993
9:35092549:G:T	F446L	0.993
9:35092551:A:G	F446L	0.993
9:35095165:C:G	R134P	0.993
9:35089386:G:T	A1045D	0.992
9:35093132:A:C	N339K	0.992
9:35093132:A:T	N339K	0.992
9:35089399:A:G	W1041R	0.991
9:35089399:A:T	W1041R	0.991
9:35090637:A:G	W895R	0.991
9:35090637:A:T	W895R	0.991
9:35093527:T:G	H278P	0.991
9:35093975:G:C	D235E	0.991
9:35093975:G:T	D235E	0.991
9:35095483:A:G	F28S	0.991
9:35089397:C:A	W1041C	0.990
9:35089397:C:G	W1041C	0.990
9:35093525:C:A	G279W	0.990
9:35094339:C:G	G178R	0.990
9:35094339:C:T	G178R	0.990

dbSNP variants (sampled 300 via entrez): RS1000364291 (9:35093020 G>A,C), RS1000521352 (9:35097572 T>C), RS1000904864 (9:35097762 G>C), RS1001200895 (9:35094921 C>T), RS1002172482 (9:35096404 C>A), RS1002319990 (9:35089698 C>G), RS1002579515 (9:35094682 C>T), RS1002652320 (9:35096217 C>T), RS1002702535 (9:35098244 C>T), RS1003205614 (9:35097873 G>T), RS1004636526 (9:35088645 A>G), RS1005158118 (9:35098455 C>T), RS1005354455 (9:35096852 C>T), RS1005561376 (9:35098236 T>C), RS1006221471 (9:35090074 C>T)

Disease associations

OMIM: gene MIM:614730 | disease phenotypes: MIM:614749, MIM:239300, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperphosphatasia with intellectual disability syndrome 2	Definitive	Autosomal recessive
hyperphosphatasia-intellectual disability syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AR

Mondo (5): hyperphosphatasia with intellectual disability syndrome 2 (MONDO:0013882), hyperphosphatasia-intellectual disability syndrome (MONDO:0016596), intellectual disability (MONDO:0001071), Hirschsprung disease (MONDO:0018309), hyperphosphatasia with intellectual disability syndrome 1 (MONDO:0009398)

Orphanet (3): Hyperphosphatasia-intellectual disability syndrome (Orphanet:247262), Hirschsprung disease (Orphanet:388), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

82 total (30 of 82 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000303	Mandibular prognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000378	Cupped ear
HP:0000391	Thickened helices
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000470	Short neck
HP:0000540	Hypermetropia
HP:0000565	Esotropia
HP:0000582	Upslanted palpebral fissure
HP:0000594	Shallow anterior chamber
HP:0000637	Long palpebral fissure
HP:0000657	Oculomotor apraxia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006295_14	Response to quetiapine in schizophrenia	9.000000e-06
GCST012317_12	Triglyceride levels x SSRI levels (escitalopram or citalopram) interaction in schizophrenia or bipolar disorder	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067267 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.87	Kd	134.2	nM	CHEMBL5653589
6.63	ED50	233.2	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149005: Binding affinity to human PIGO incubated for 45 mins by Kinobead based pull down assay	kd	0.1342	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
aristolochic acid I	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
CGP 52608	increases reaction, affects binding	1
abrine	increases expression	1
jinfukang	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cadmium	affects expression	1
Doxorubicin	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methotrexate	decreases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Thiram	decreases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652047	Binding	Binding affinity to human PIGO incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9N3	Ubigene HEK293 PIGO KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD