PIGG

Summary

PIGG (phosphatidylinositol glycan anchor biosynthesis class G (EMM blood group), HGNC:25985) is a protein-coding gene on chromosome 4p16.3, encoding GPI ethanolamine phosphate transferase 2, catalytic subunit (Q5H8A4). Catalytic subunit of the ethanolamine phosphate transferase 2 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the second alpha-1,6-linked mannose of a 2-acyl-6-[6-phosphoethanolamine-alpha-D-mannosyl-(1->2)-alp….

This gene encodes an enzyme involved in glycosylphosphatidylinositol-anchor biosynthesis. The encoded protein, which is localized to the endoplasmic reticulum, is involved in transferring ethanoloamine phosphate to mannose 2 of glycosylphosphatidylinositol species H7 to form species H8. Allelic variants of this gene have been associated with intellectual disability, hypotonia, and early-onset seizures. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 54872 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal recessive 53 (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 1,166 total — 61 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 131
• MANE Select transcript: NM_001127178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25985
Approved symbol	PIGG
Name	phosphatidylinositol glycan anchor biosynthesis class G (EMM blood group)
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20265, GPI7, LAS21
Ensembl gene	ENSG00000174227
Ensembl biotype	protein_coding
OMIM	616918
Entrez	54872

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 11 protein_coding_CDS_not_defined, 10 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay

ENST00000310340, ENST00000383028, ENST00000453061, ENST00000502311, ENST00000503111, ENST00000503261, ENST00000504187, ENST00000504346, ENST00000504879, ENST00000505800, ENST00000506402, ENST00000506898, ENST00000507493, ENST00000508144, ENST00000508562, ENST00000508669, ENST00000509768, ENST00000510235, ENST00000511247, ENST00000511448, ENST00000511666, ENST00000513192, ENST00000513239, ENST00000513679, ENST00000514953, ENST00000515237, ENST00000868086, ENST00000868087, ENST00000936869

RefSeq mRNA: 14 — MANE Select: NM_001127178 NM_001127178, NM_001289051, NM_001289052, NM_001289053, NM_001289055, NM_001289057, NM_001345986, NM_001345987, NM_001345988, NM_001345989, NM_001345990, NM_001345991, NM_001345994, NM_017733

CCDS: CCDS3336, CCDS46992, CCDS75080, CCDS75081, CCDS75082, CCDS75083

Canonical transcript exons

ENST00000453061 — 13 exons

Exon	Start	End
ENSE00003459664	521056	521273
ENSE00003523488	533818	533981
ENSE00003537250	507405	507593
ENSE00003537912	515973	516185
ENSE00003543484	500396	500601
ENSE00003557649	530436	530745
ENSE00003606754	508829	508970
ENSE00003607350	499210	499489
ENSE00003653960	527039	527230
ENSE00003670646	521660	521941
ENSE00003672801	523459	523913
ENSE00003672922	505718	505927
ENSE00003844913	539153	540200

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 96.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.7130 / max 238.8242, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46491	29.9165	1821
46492	1.7965	797

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.99	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.76	gold quality
lower esophagus	UBERON:0013473	96.68	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.68	gold quality
mucosa of stomach	UBERON:0001199	96.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.41	gold quality
pancreatic ductal cell	CL:0002079	96.19	gold quality
adenohypophysis	UBERON:0002196	95.93	gold quality
left ovary	UBERON:0002119	95.91	gold quality
right ovary	UBERON:0002118	95.88	gold quality
left lobe of thyroid gland	UBERON:0001120	95.77	gold quality
right lobe of thyroid gland	UBERON:0001119	95.76	gold quality
body of uterus	UBERON:0009853	95.64	gold quality
pituitary gland	UBERON:0000007	95.34	gold quality
skin of abdomen	UBERON:0001416	95.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.30	gold quality
tibial nerve	UBERON:0001323	95.29	gold quality
metanephros cortex	UBERON:0010533	95.28	gold quality
lower esophagus mucosa	UBERON:0035834	95.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.12	gold quality
skin of leg	UBERON:0001511	95.06	gold quality
thyroid gland	UBERON:0002046	95.05	gold quality
transverse colon	UBERON:0001157	94.87	gold quality
cerebellar hemisphere	UBERON:0002245	94.84	gold quality
endocervix	UBERON:0000458	94.79	gold quality
body of stomach	UBERON:0001161	94.69	gold quality
cerebellar cortex	UBERON:0002129	94.69	gold quality
left uterine tube	UBERON:0001303	94.55	gold quality
popliteal artery	UBERON:0002250	94.54	gold quality
tibial artery	UBERON:0007610	94.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

60 targeting PIGG, 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-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-6513-3P	99.59	69.77	1102

Literature-anchored findings (GeneRIF, showing 4)

• loss-of-function variants in PIGG associated with intellectual disability and hypotonia (PMID:26996948)
• Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an intellectual disability syndrome, and we find that loss of function of PIGG is associated with Glycosylphosphatidylinositol deficiency (PMID:28581210)
• Arg658Gln mutation segregates with nonsyndromic intellectual disability in Iranian family. (PMID:31414351)
• PIGG variant pathogenicity assessment reveals characteristic features within 19 families. (PMID:34113002)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pigg	ENSDARG00000038270
mus_musculus	Pigg	ENSMUSG00000029263
rattus_norvegicus	Pigg	ENSRNOG00000071170
drosophila_melanogaster	PIG-G	FBGN0033187
caenorhabditis_elegans		WBGENE00009204

Protein

Protein identifiers

GPI ethanolamine phosphate transferase 2, catalytic subunit — Q5H8A4 (reviewed: Q5H8A4)

Alternative names: GPI7 homolog, Phosphatidylinositol-glycan biosynthesis class G protein

All UniProt accessions (7): Q5H8A4, D6R9J9, D6RC16, D6RD39, D6RFE8, E7EM50, E7EWV1

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the ethanolamine phosphate transferase 2 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the second alpha-1,6-linked mannose of 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) intermediate to generate a 2-acyl-6-[6-phosphoethanolamine-alpha-D-mannosyl-(1->2)-6-phosphoethanolamine-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 H8) and participates in the eleventh step of the glycosylphosphatidylinositol-anchor biosynthesis.

Subunit / interactions. Part of the ethanolamine phosphate transferase 2 complex composed by PIGG and PIGF. PIGF is required to stabilize it. Competes with PIGO for the binding of PIGF.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy (NEDHSCA) [MIM:616917] An autosomal recessive disorder characterized by delayed psychomotor development, hypotonia, and early-onset seizures in most patients. Additional variable features are cerebellar atrophy, ataxia, and non-specific dysmorphic features. Some patients may have the Emm-null blood group phenotype. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor biosynthesis.

Polymorphism. Genetic variations in PIGG define the Emm blood group system [MIM:619812].

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

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

Isoforms (6)

UniProt ID	Names	Canonical?
Q5H8A4-1	1	yes
Q5H8A4-2	2
Q5H8A4-3	3
Q5H8A4-4	4
Q5H8A4-5	5
Q5H8A4-6	6

RefSeq proteins (14): NP_001120650, NP_001275980, NP_001275981, NP_001275982, NP_001275984, NP_001275986, NP_001332915, NP_001332916, NP_001332917, NP_001332918, NP_001332919, NP_001332920, NP_001332923, NP_060203 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002591	Phosphodiest/P_Trfase	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR037674	PIG-G_N	Domain
IPR039527	PIGG/GPI7	Family
IPR045687	PIGG/GPI7_C	Domain

Pfam: PF01663, PF19316

Catalyzed reactions (Rhea), 1 shown:

• 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-glycero-3-phosphoethanolamine = a 2-acyl-6-[6-phosphoethanolamine-alpha-D-mannosyl-(1->2)-6-phosphoethanolamine-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:61016)

UniProt features (52 total): sequence variant 26, transmembrane region 12, splice variant 9, sequence conflict 2, chain 1, topological domain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5H8A4-F1	83.48	0.49

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): 194

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 372 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, REACTOME_SYNTHESIS_OF_GLYCOSYLPHOSPHATIDYLINOSITOL_GPI, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_PROTEIN_MATURATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, MODULE_206, KEGG_GLYCOSYLPHOSPHATIDYLINOSITOL_GPI_ANCHOR_BIOSYNTHESIS, chr4p16, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS

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

GO Molecular Function (4): transferase activity (GO:0016740), phosphotransferase activity, for other substituted phosphate groups (GO:0016780), obsolete CP2 mannose-ethanolamine phosphotransferase activity (GO:0051267), mannose-ethanolamine phosphotransferase activity (GO:0051377)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

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
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
phosphotransferase activity, for other substituted phosphate groups	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1306 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIGG	PIGA	P37287	874
PIGG	PIGM	Q9H3S5	844
PIGG	PIGB	Q92521	816
PIGG	PIGH	Q14442	811
PIGG	PIGC	Q92535	811
PIGG	PIGL	Q9Y2B2	806
PIGG	PIGV	Q9NUD9	775
PIGG	PIGK	Q92643	765
PIGG	PIGZ	Q86VD9	742
PIGG	PIGW	Q7Z7B1	737
PIGG	PIGT	Q969N2	735
PIGG	PIGP	P57054	716
PIGG	PIGY	Q3MUY2	693
PIGG	PIGQ	Q9BRB3	685
PIGG	PGAP2	Q9UHJ9	683

IntAct

86 interactions, top by confidence:

A	B	Type	Score
B3GAT3	GOLIM4	psi-mi:“MI:0914”(association)	0.640
FPR2	ARL6IP5	psi-mi:“MI:0914”(association)	0.640
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
CCR6	PODXL	psi-mi:“MI:0914”(association)	0.530
GPR17	IPO8	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
CTLA4	B4GALT5	psi-mi:“MI:0914”(association)	0.530
OPALIN	BTAF1	psi-mi:“MI:0914”(association)	0.530
PIGG	GLP1R	psi-mi:“MI:0915”(physical association)	0.510
PIGG	SERPINH1	psi-mi:“MI:0915”(physical association)	0.400
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
PIGG	DRD2	psi-mi:“MI:0915”(physical association)	0.370
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
M	TM9SF1	psi-mi:“MI:0914”(association)	0.350
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
TMED10	PGRMC1	psi-mi:“MI:0914”(association)	0.350
ATP6V0E1	ATP6AP2	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
ADGRE5	TMEM223	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350

BioGRID (92): PIGG (Affinity Capture-MS), PIGG (Affinity Capture-MS), PIGG (Affinity Capture-MS), PIGG (Affinity Capture-MS), PIGG (Affinity Capture-MS), PIGG (Affinity Capture-MS), PIGG (Proximity Label-MS), PIGG (Proximity Label-MS), PIGG (Proximity Label-MS), PIGG (Proximity Label-MS), PIGG (Proximity Label-MS), PIGG (Proximity Label-MS), PIGG (Affinity Capture-MS), PIGG (Two-hybrid), PIGG (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GVZ9, A4IFN5, A5PK40, A6NH52, A6NI61, B2LYG4, B2RZC9, B6ID01, D2HKB0, D3ZG27, P86229, Q0VDI3, Q15012, Q15546, Q17QJ2, Q1RLT2, Q2TA01, Q4R4I5, Q4R6E8, Q5H8A4, Q5R7Q1, Q5RAH0, Q5RL79, Q5U3C3, Q5VTY9, Q5ZML7, Q64232, Q6PHN7, Q6QRN8, Q719N3, Q71SV0, Q8BWB6, Q8IY49, Q8N6M3, Q8NFT2, Q8R189, Q8VD53, Q8VDI9, Q8VDR5, Q9CQC4

Diamond homologs: O13663, P40367, Q07830, Q09782, Q2U9J2, Q4WDM5, Q5H8A4, Q6BZ57, Q6C7Q6, Q6CLN2, Q6FPB2, Q74ZS2, Q758B8, Q8TEQ8, Q8TGB2, Q9JJI6, O95427, Q9R1S3, Q4W9R7, Q5AXD1, Q757X5

SIGNOR signaling

2 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 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
Chemokine receptors bind chemokines	5	12.7×	4e-03
Class A/1 (Rhodopsin-like receptors)	8	8.0×	2e-03
GPCR ligand binding	8	6.9×	2e-03
G alpha (i) signalling events	9	4.7×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cytosolic calcium ion concentration	13	14.9×	2e-09
calcium-mediated signaling	6	10.8×	3e-03
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	5	10.7×	9e-03
adenylate cyclase-activating G protein-coupled receptor signaling pathway	9	10.0×	7e-05
phospholipase C-activating G protein-coupled receptor signaling pathway	6	7.7×	9e-03
G protein-coupled receptor signaling pathway	19	6.8×	1e-08
cell surface receptor signaling pathway	10	6.3×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1166 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	61
Likely pathogenic	22
Uncertain significance	516
Likely benign	447
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033708	NM_001127178.3(PIGG):c.2872G>T (p.Glu958Ter)	Pathogenic
1069220	NM_001127178.3(PIGG):c.309_310del (p.His103fs)	Pathogenic
1070070	NM_001127178.3(PIGG):c.2288_2289del (p.Tyr763fs)	Pathogenic
1070171	NM_001127178.3(PIGG):c.624G>A (p.Trp208Ter)	Pathogenic
1214420	NM_001127178.3(PIGG):c.1210del (p.Leu404fs)	Pathogenic
1381176	NM_001127178.3(PIGG):c.1173_1174del (p.Tyr392fs)	Pathogenic
1387516	NM_001127178.3(PIGG):c.1544_1545del (p.Ala515fs)	Pathogenic
1396893	NM_001127178.3(PIGG):c.1803del (p.Asp601fs)	Pathogenic
1401894	NM_001127178.3(PIGG):c.623G>A (p.Trp208Ter)	Pathogenic
1407970	NC_000004.11:g.(?502598)(509994_?)del	Pathogenic
1412317	NM_001127178.3(PIGG):c.1733_1734del (p.Trp578fs)	Pathogenic
1453486	NM_001127178.3(PIGG):c.901+1del	Pathogenic
1453903	NM_001127178.3(PIGG):c.1923dup (p.Thr642fs)	Pathogenic
1457020	NM_001127178.3(PIGG):c.785del (p.Leu262fs)	Pathogenic
1458529	NM_001127178.3(PIGG):c.352C>T (p.Arg118Ter)	Pathogenic
1459106	NM_001127178.3(PIGG):c.571del	Pathogenic
1686805	NM_001127178.3(PIGG):c.155-215_570+216del	Pathogenic
1686806	NM_001127178.3(PIGG):c.1114+2230_2069+847del	Pathogenic
1686807	NM_001127178.3(PIGG):c.361-51_383delinsGACTT	Pathogenic
1686808	NM_001127178.3(PIGG):c.1640G>A (p.Trp547Ter)	Pathogenic
1686809	NM_001127178.3(PIGG):c.640C>T (p.His214Tyr)	Pathogenic
1805898	NM_001127178.3(PIGG):c.1193C>G (p.Ser398Ter)	Pathogenic
2005199	NM_001127178.3(PIGG):c.2129_2130del (p.Val710fs)	Pathogenic
2014469	NM_001127178.3(PIGG):c.768_769del (p.Glu256fs)	Pathogenic
2061428	NM_001127178.3(PIGG):c.2334del (p.Lys779fs)	Pathogenic
2080198	NM_001127178.3(PIGG):c.1562_1563del (p.Val521fs)	Pathogenic
2106191	NM_001127178.3(PIGG):c.2294_2295del (p.Phe765fs)	Pathogenic
2112471	NM_001127178.3(PIGG):c.2444del (p.Pro815fs)	Pathogenic
2194645	NM_001127178.3(PIGG):c.1702dup (p.Ser568fs)	Pathogenic
225637	NM_001127178.3(PIGG):c.928C>T (p.Gln310Ter)	Pathogenic

SpliceAI

3413 predictions. Top by Δscore:

Variant	Effect	Δscore
4:500386:A:AG	acceptor_gain	1.0000
4:500599:AAGGT:A	donor_loss	1.0000
4:500602:GTAA:G	donor_loss	1.0000
4:500603:T:A	donor_loss	1.0000
4:505712:CTGCA:C	acceptor_loss	1.0000
4:505713:TGCAG:T	acceptor_loss	1.0000
4:505714:GCAGG:G	acceptor_loss	1.0000
4:505715:CA:C	acceptor_loss	1.0000
4:505716:A:AG	acceptor_gain	1.0000
4:505716:A:C	acceptor_loss	1.0000
4:505717:G:GA	acceptor_gain	1.0000
4:505717:GGC:G	acceptor_gain	1.0000
4:505717:GGCA:G	acceptor_gain	1.0000
4:505717:GGCAT:G	acceptor_gain	1.0000
4:505925:GAG:G	donor_gain	1.0000
4:505928:GTC:G	donor_loss	1.0000
4:505929:T:A	donor_loss	1.0000
4:516113:T:G	donor_gain	1.0000
4:521222:GGCCC:G	donor_gain	1.0000
4:521228:G:GG	donor_gain	1.0000
4:521271:G:GT	donor_gain	1.0000
4:527033:TTTCA:T	acceptor_loss	1.0000
4:527034:TTCA:T	acceptor_loss	1.0000
4:527036:CA:C	acceptor_loss	1.0000
4:527037:A:AC	acceptor_loss	1.0000
4:527037:A:AG	acceptor_gain	1.0000
4:527038:G:GA	acceptor_gain	1.0000
4:527038:GCT:G	acceptor_gain	1.0000
4:527038:GCTCT:G	acceptor_gain	1.0000
4:527231:G:A	donor_loss	1.0000

AlphaMissense

6349 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:505853:T:A	W166R	0.998
4:505853:T:C	W166R	0.998
4:507541:T:C	L236P	0.997
4:505842:G:A	G162E	0.996
4:507408:G:C	D192H	0.996
4:507490:A:T	D219V	0.996
4:505842:G:T	G162V	0.995
4:523534:A:C	S564R	0.995
4:523536:C:A	S564R	0.995
4:523536:C:G	S564R	0.995
4:523549:A:C	S569R	0.995
4:523551:C:A	S569R	0.995
4:523551:C:G	S569R	0.995
4:500582:T:A	V114D	0.994
4:507483:G:T	G217W	0.994
4:507490:A:C	D219A	0.994
4:507409:A:T	D192V	0.993
4:507418:T:A	V195D	0.993
4:507474:C:G	H214D	0.993
4:507483:G:A	G217R	0.993
4:507483:G:C	G217R	0.993
4:523546:A:C	S568R	0.993
4:523548:C:A	S568R	0.993
4:523548:C:G	S568R	0.993
4:539262:A:C	S949R	0.993
4:539264:T:A	S949R	0.993
4:539264:T:G	S949R	0.993
4:499402:T:C	F23L	0.992
4:499404:C:A	F23L	0.992
4:499404:C:G	F23L	0.992

dbSNP variants (sampled 300 via entrez): RS1000001504 (4:526482 GC>G), RS1000025066 (4:536589 C>T), RS1000031559 (4:498967 G>A,C), RS1000058958 (4:504634 G>T), RS1000078462 (4:536780 G>A), RS1000120870 (4:525140 A>T), RS1000229852 (4:532788 C>T), RS1000234937 (4:524754 A>G,T), RS1000325315 (4:515206 C>T), RS1000417972 (4:522637 C>T), RS1000583367 (4:538681 C>A), RS1000660209 (4:518524 C>T), RS1000682548 (4:512995 T>C), RS1000691717 (4:532941 G>A), RS1000766058 (4:514605 T>C)

Disease associations

OMIM: gene MIM:616918 | disease phenotypes: MIM:616917, MIM:239300

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 53	Definitive	Autosomal recessive

Mondo (2): intellectual disability, autosomal recessive 53 (MONDO:0014832), hyperphosphatasia with intellectual disability syndrome 1 (MONDO:0009398)

Orphanet (2): Early-onset epilepsy-intellectual disability-brain anomalies syndrome (Orphanet:488635), Hyperphosphatasia-intellectual disability syndrome (Orphanet:247262)

HPO phenotypes

131 total (30 of 131 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000077	Abnormality of the kidney
HP:0000078	Abnormality of the genital system
HP:0000079	Abnormality of the urinary system
HP:0000151	Aplasia of the uterus
HP:0000153	Abnormality of the mouth
HP:0000159	Abnormal lip morphology
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000288	Abnormality of the philtrum
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000485	Megalocornea
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006633_8	Initial alcohol sensitivity	7.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
beta-lapachone	increases expression, decreases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects cotreatment, decreases methylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects methylation	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Selenium	decreases expression	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
Vitamin E	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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