PIGS

Summary

PIGS (phosphatidylinositol glycan anchor biosynthesis class S, HGNC:14937) is a protein-coding gene on chromosome 17q11.2, encoding GPI-anchor transamidase component PIGS (Q96S52). Component of the glycosylphosphatidylinositol-anchor (GPI-anchor) transamidase (GPI-T) complex that catalyzes the formation of the linkage between a proprotein and a GPI-anchor and participates in GPI anchored protein biosynthesis. It is a selective cancer dependency (DepMap: 12.0% of cell lines).

This gene encodes a protein that is involved in GPI-anchor biosynthesis. The glycosylphosphatidylinositol (GPI) anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins.

Source: NCBI Gene 94005 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycosylphosphatidylinositol biosynthesis defect 18 (Definitive, ClinGen)
• Clinical variants (ClinVar): 164 total — 8 pathogenic, 8 likely-pathogenic
• GTEx eGene: eQTL in 19 tissues, sQTL in 7 (q < 0.05)
• Phenotypes (HPO): 64
• Cancer dependency (DepMap): dependent in 12.0% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.76 (unconstrained)
• MANE Select transcript: NM_033198

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14937
Approved symbol	PIGS
Name	phosphatidylinositol glycan anchor biosynthesis class S
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	PIG-S
Ensembl gene	ENSG00000087111
Ensembl biotype	protein_coding
OMIM	610271
Entrez	94005

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 22 nonsense_mediated_decay, 11 protein_coding, 10 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000308360

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 4, TSL 3: 2, TSL 4: 4, TSL 5: 2

ENST00000308360, ENST00000268758, ENST00000395346, ENST00000465444, ENST00000484580, ENST00000487231, ENST00000492429, ENST00000577594, ENST00000577620, ENST00000580968, ENST00000582615, ENST00000582721, ENST00000583631, ENST00000584080, ENST00000584413, ENST00000706175, ENST00000706176, ENST00000706177, ENST00000706178, ENST00000706179, ENST00000706180, ENST00000706181, ENST00000706182, ENST00000706183, ENST00000706184, ENST00000706185, ENST00000706186, ENST00000706187, ENST00000706188, ENST00000706189, ENST00000706190, ENST00000706191, ENST00000706192, ENST00000706193, ENST00000706194, ENST00000896504, ENST00000931672, ENST00000931673, ENST00000954253, ENST00001006917, ENST00001006918, ENST00001055030, ENST00001088576, ENST00001091359, ENST00001125017, ENST00001143380

RefSeq mRNA: 1 — MANE Select: NM_033198 NM_033198

CCDS: CCDS11235

Canonical transcript exons

ENST00000308360 — 12 exons

Exon	Start	End
ENSE00002695279	28571463	28571524
ENSE00003474353	28563431	28563522
ENSE00003514926	28561422	28561629
ENSE00003540786	28553387	28554495
ENSE00003544800	28570852	28570963
ENSE00003586015	28563818	28563907
ENSE00003600846	28556166	28556266
ENSE00003623061	28554851	28555061
ENSE00003656403	28571049	28571188
ENSE00003657808	28556827	28556972
ENSE00003665850	28560049	28560191
ENSE00003680101	28558476	28558590

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 94.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.4930 / max 155.4419, expressed in 1817 samples.

Highest expression (Bgee): stromal cell of endometrium, granulocyte, islet of Langerhans, mucosa of transverse colon, rectum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PIGS is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 26 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellar Hemisphere	sqtl	2.9e-11	-0.57	17:28560970:T:A
Brain Cerebellum	sqtl	1.5e-08	-0.44	17:28556295:A:G
Brain Frontal Cortex BA9	eqtl	1.2e-07	+0.28	17:28654853:A:G
Nerve Tibial	sqtl	2.8e-05	-0.31	17:28654853:A:G
Muscle Skeletal	eqtl	6.6e-05	+0.23	17:28780841:C:G
Skin Sun Exposed Lower leg	sqtl	7.7e-05	-0.29	17:28640944:A:C
Cells EBV-transformed lymphocytes	eqtl	2.1e-04	-1.26	17:29236837:C:A
Artery Tibial	eqtl	7.6e-04	-0.10	17:28677685:C:A
Artery Tibial	sqtl	2.6e-03	-0.27	17:28556295:A:G
Whole Blood	eqtl	2.7e-03	-0.20	17:28734253:G:A
Colon Transverse	eqtl	4.5e-03	+0.09	17:28056934:C:T
Skin Not Sun Exposed Suprapubic	eqtl	6.1e-03	-0.30	17:28541509:A:AT
Skin Sun Exposed Lower leg	eqtl	7.5e-03	-0.24	17:28541509:A:AT
Small Intestine Terminal Ileum	eqtl	8.7e-03	-0.80	17:29236837:C:A
Artery Aorta	sqtl	1.7e-02	-0.28	17:28560970:T:A
Brain Cortex	eqtl	1.8e-02	+0.18	17:28654853:A:G
Artery Coronary	eqtl	1.8e-02	+0.48	17:29313280:T:C
Brain Anterior cingulate cortex BA24	eqtl	2.3e-02	+0.19	17:28560970:T:A
Thyroid	eqtl	2.5e-02	+0.25	17:29367314:C:T
Esophagus Gastroesophageal Junction	eqtl	2.7e-02	-0.44	17:27982759:G:A

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
165031	39.5259	1817
165024	0.2924	127
165030	0.2808	129
165029	0.2510	136
165025	0.0538	10
165027	0.0480	16
165026	0.0335	6
165028	0.0076	2

Top tissues by expression

showing 100 of 141 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	94.71	gold quality
granulocyte	CL:0000094	93.92	gold quality
islet of Langerhans	UBERON:0000006	93.07	gold quality
mucosa of transverse colon	UBERON:0004991	92.92	gold quality
rectum	UBERON:0001052	92.66	gold quality
duodenum	UBERON:0002114	92.20	gold quality
leukocyte	CL:0000738	92.11	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.11	gold quality
monocyte	CL:0000576	91.94	gold quality
heart left ventricle	UBERON:0002084	91.93	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.92	gold quality
metanephros cortex	UBERON:0010533	91.88	gold quality
cerebellum	UBERON:0002037	91.83	gold quality
cerebellar hemisphere	UBERON:0002245	91.82	gold quality
cerebellar cortex	UBERON:0002129	91.80	gold quality
blood	UBERON:0000178	91.79	gold quality
small intestine	UBERON:0002108	91.78	gold quality
apex of heart	UBERON:0002098	91.75	gold quality
skin of leg	UBERON:0001511	91.73	gold quality
transverse colon	UBERON:0001157	91.71	gold quality
adult mammalian kidney	UBERON:0000082	91.53	gold quality
zone of skin	UBERON:0000014	91.44	gold quality
esophagus mucosa	UBERON:0002469	91.29	gold quality
gastrocnemius	UBERON:0001388	91.23	gold quality
bone element	UBERON:0001474	91.18	gold quality
bone marrow	UBERON:0002371	91.18	gold quality
spleen	UBERON:0002106	91.12	gold quality
skin of abdomen	UBERON:0001416	91.10	gold quality
body of stomach	UBERON:0001161	90.90	gold quality
kidney	UBERON:0002113	90.88	gold quality
muscle of leg	UBERON:0001383	90.85	gold quality
esophagus	UBERON:0001043	90.82	gold quality
skeletal muscle organ	UBERON:0014892	90.81	gold quality
heart	UBERON:0000948	90.80	gold quality
intestine	UBERON:0000160	90.74	gold quality
right lung	UBERON:0002167	90.74	gold quality
descending thoracic aorta	UBERON:0002345	90.72	gold quality
popliteal artery	UBERON:0002250	90.63	gold quality
smooth muscle tissue	UBERON:0001135	90.62	gold quality
tibial artery	UBERON:0007610	90.62	gold quality
colon	UBERON:0001155	90.57	gold quality
left coronary artery	UBERON:0001626	90.57	gold quality
right coronary artery	UBERON:0001625	90.53	gold quality
cortex of kidney	UBERON:0001225	90.45	gold quality
upper lobe of left lung	UBERON:0008952	90.42	gold quality
lower esophagus	UBERON:0013473	90.40	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.40	gold quality
mucosa of stomach	UBERON:0001199	90.37	gold quality
tibial nerve	UBERON:0001323	90.37	gold quality
thoracic aorta	UBERON:0001515	90.35	gold quality
placenta	UBERON:0001987	90.30	gold quality
left lobe of thyroid gland	UBERON:0001120	90.26	gold quality
ascending aorta	UBERON:0001496	90.26	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.25	gold quality
right lobe of thyroid gland	UBERON:0001119	90.19	gold quality
prefrontal cortex	UBERON:0000451	90.16	gold quality
thyroid gland	UBERON:0002046	90.07	gold quality
muscle tissue	UBERON:0002385	90.06	gold quality
lower esophagus mucosa	UBERON:0035834	90.06	gold quality
stomach	UBERON:0000945	89.97	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.94	gold quality
left adrenal gland	UBERON:0001234	89.86	gold quality
frontal cortex	UBERON:0001870	89.86	gold quality
material anatomical entity	UBERON:0000465	89.83	gold quality
anatomical system	UBERON:0000467	89.83	gold quality
multicellular organism	UBERON:0000468	89.83	gold quality
lymph node	UBERON:0000029	89.79	gold quality
adipose tissue	UBERON:0001013	89.76	gold quality
vermiform appendix	UBERON:0001154	89.76	gold quality
right adrenal gland	UBERON:0001233	89.71	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.68	gold quality
minor salivary gland	UBERON:0001830	89.66	gold quality
left adrenal gland cortex	UBERON:0035825	89.65	gold quality
skeletal muscle tissue	UBERON:0001134	89.64	gold quality
fallopian tube	UBERON:0003889	89.64	gold quality
right atrium auricular region	UBERON:0006631	89.64	gold quality
fundus of stomach	UBERON:0001160	89.60	gold quality
right frontal lobe	UBERON:0002810	89.57	gold quality
vagina	UBERON:0000996	89.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.54	gold quality
bone marrow cell	CL:0002092	89.51	gold quality
breast	UBERON:0000310	89.49	gold quality
mammary gland	UBERON:0001911	89.49	gold quality
thoracic mammary gland	UBERON:0005200	89.49	gold quality
right adrenal gland cortex	UBERON:0035827	89.47	gold quality
adrenal gland	UBERON:0002369	89.46	gold quality
saliva-secreting gland	UBERON:0001044	89.45	gold quality
lung	UBERON:0002048	89.44	gold quality
urinary bladder	UBERON:0001255	89.37	gold quality
pancreas	UBERON:0001264	89.18	gold quality
omental fat pad	UBERON:0010414	89.06	gold quality
ectocervix	UBERON:0012249	89.04	gold quality
anterior cingulate cortex	UBERON:0009835	88.96	gold quality
prostate gland	UBERON:0002367	88.89	gold quality
superior frontal gyrus	UBERON:0002661	88.82	gold quality
cerebral cortex	UBERON:0000956	88.81	gold quality
left uterine tube	UBERON:0001303	88.80	gold quality
brain	UBERON:0000955	88.73	gold quality
right ovary	UBERON:0002118	88.59	gold quality
adrenal tissue	UBERON:0018303	88.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-10	no	151.18
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Frontal cortex	tissue	45.8
Caudate putamen	tissue	45.2
Choroid plexus	tissue	32.6
Small intestine	tissue	28.0	not detected
Duodenum	tissue	27.6	not detected
Skeletal muscle	tissue	26.7	not detected
Parathyroid gland	tissue	26.0	medium
Hippocampal formation	tissue	23.6
Colon	tissue	23.1	not detected
Stomach 1	tissue	22.5	low
Heart muscle	tissue	22.0	low
Spinal cord	tissue	22.0
Thyroid gland	tissue	21.8	low
Substantia nigra	tissue	21.7
Adipose tissue	tissue	21.5	not detected
Pons	tissue	21.2
Esophagus	tissue	21.1	not detected
Medulla oblongata	tissue	20.5
Midbrain	tissue	20.4
Cerebral cortex	tissue	20.3	medium
Superior colliculi	tissue	20.3
Somatosensory cortex	tissue	20.3
Periaqueductal gray	tissue	19.8
Thalamus	tissue	19.3
Amygdala	tissue	19.2
Hypothalamus	tissue	18.7
Fallopian tube	tissue	18.4	medium
Temporal cortex	tissue	18.1
Prefrontal cortex	tissue	17.9
Motor cortex	tissue	17.6
Lung	tissue	17.6	high
Tongue	tissue	17.5
Insular cortex	tissue	17.5
Retrosplenial and cingulate cortex	tissue	17.4
Entorhinal cortex	tissue	17.1
Bone marrow	tissue	17.0	medium
Ventral forebrain	tissue	17.0
Septum	tissue	16.7
Occipital cortex	tissue	16.6
Cerebellum	tissue	16.5	medium
Retrosplenial cortex	tissue	16.5
Basal ganglia	tissue	16.3	medium
Hippocampus	tissue	16.0	low
Vagina	tissue	15.9	not detected
Urinary bladder	tissue	15.8	medium
Lymph node	tissue	15.7	not detected
Thymus	tissue	15.3
Putamen	tissue	15.2
Prostate	tissue	15.2	low
Placenta	tissue	15.1	low
Spleen	tissue	15.0	medium
Skin 1	tissue	14.9	low
Pancreas	tissue	14.8	medium
Kidney	tissue	14.8	medium
Seminal vesicle	tissue	14.6	not detected
Smooth muscle	tissue	14.6	not detected
Rectum	tissue	14.2	low
Adrenal gland	tissue	13.7	medium
Gallbladder	tissue	13.5	medium
Appendix	tissue	13.3	low

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Ventral hippocampus (23.6), Ventral spinal cord (22.0), Blood vessel (21.8), Subiculum (21.5), Dorsal hippocampus (21.1).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting PIGS by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 55 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870

Functional genomics

gnomAD constraint: pLI 4.92e-06, LOEUF 0.76, missense Z 1.59 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000308360 — one region, missense o/e 0.88. DepMap (CRISPR cell-line fitness): dependent in 12.0% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): BPH-1 (-1.459), MFM-223 (-0.923), NCI-H23 (-0.914), MGH-ICC9 (-0.824), NCI-H2122 (-0.818), HT-1197 (-0.796), AM-38 (-0.795), Mero-41 (-0.793), YKG1 (-0.773), BICR 56 (-0.747), G-402 (-0.738), LO68 (-0.733), BHT-101 (-0.731), Lu-65 (-0.731), UM-UC-1 (-0.731).

Literature-anchored findings (GeneRIF, showing 2)

• By describing the consequences of PIGS disruption in humans and extending the family of IGDs. (PMID:30269814)
• Expanding the phenotype of PIGS-associated early onset epileptic developmental encephalopathy. (PMID:33410539)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pigs	ENSDARG00000017813
mus_musculus	Pigs	ENSMUSG00000041958
rattus_norvegicus	Pigs	ENSRNOG00000011366
drosophila_melanogaster	PIG-S	FBGN0265190
caenorhabditis_elegans		WBGENE00011776

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q3SZL5	91.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SPAG5-AS1	ncRNA	100506436
RSKR	protein-coding	124923
ALDOC	protein-coding	230
BLTP2	protein-coding	9703
FOXN1	protein-coding	8456
SLC13A2	protein-coding	9058
UNC119	protein-coding	9094
SPAG5	protein-coding	10615

Protein

Protein identifiers

GPI-anchor transamidase component PIGS — Q96S52 (reviewed: Q96S52)

Alternative names: Phosphatidylinositol-glycan biosynthesis class S protein

All UniProt accessions (21): A0A994J546, A0A994J550, A0A994J555, A0A994J5E2, A0A994J5E6, A0A994J5F0, A0A994J5F5, A0A994J5S0, A0A994J5S5, A0A994J5S7, A0A994J7M3, A0A994J7M6, A0A994J7M9, A0A994J801, A0A994J804, A0A994J808, A0A994J810, Q96S52, H0Y2N5, J3QL67, K7EN97

UniProt curated annotations — full annotation on UniProt →

Function. Component of the glycosylphosphatidylinositol-anchor (GPI-anchor) transamidase (GPI-T) complex that catalyzes the formation of the linkage between a proprotein and a GPI-anchor and participates in GPI anchored protein biosynthesis.

Subunit / interactions. Heteropentamer. Part of the GPI-anchor transamidase complex, consisting of PIGK, PIGT, PIGS, PIGU and GAA1.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Glycosylphosphatidylinositol biosynthesis defect 18 (GPIBD18) [MIM:618143] An autosomal recessive disorder with onset in utero or early infancy and characterized by severe global developmental delay, seizures, hypotonia, weakness, ataxia, and dysmorphic facial features. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor biosynthesis.

Similarity. Belongs to the PIGS family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96S52-1	1	yes
Q96S52-2	2

RefSeq proteins (1): NP_149975* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019540	PtdIno-glycan_biosynth_class_S	Family

Pfam: PF10510

UniProt features (90 total): helix 29, strand 23, mutagenesis site 11, turn 9, sequence variant 6, topological domain 3, glycosylation site 2, transmembrane region 2, binding site 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
7WLD	Cryo-EM structure of the human glycosylphosphatidylinositol transamidase complex at 2.53 …	ELECTRON MICROSCOPY	2.53
8IMX	Cryo-EM structure of GPI-T with a chimeric GPI-anchored protein	ELECTRON MICROSCOPY	2.85
7W72	Structure of a human glycosylphosphatidylinositol (GPI) transamidase	ELECTRON MICROSCOPY	3.1
8IMY	Cryo-EM structure of GPI-T (inactive mutant) with GPI and proULBP2, a proprotein substrate	ELECTRON MICROSCOPY	3.22

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96S52-F1	85.48	0.43

Human Protein Atlas

Protein class: Metabolic proteins, Predicted membrane proteins, Plasma proteins, Disease related genes, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of lipid/glycolipid metabolism, Epilepsy

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

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

Ligand- & substrate-binding residues (2)

Position	Role
15	a cardiolipin
18	a cardiolipin

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	370, 267

Mutagenesis-validated functional residues (11)

Position	Phenotype
43	no effect on function in gpi-anchor attachment to protein.
47	no effect on function in gpi-anchor attachment to protein.
267	no effect on function in gpi-anchor attachment to protein.
272	no effect on function in gpi-anchor attachment to protein.
276	no effect on function in gpi-anchor attachment to protein.
301	no effect on function in gpi-anchor attachment to protein.
335	no effect on function in gpi-anchor attachment to protein.
370	no effect on function in gpi-anchor attachment to protein.
444	no effect on function in gpi-anchor attachment to protein.
459–460	no effect on function in gpi-anchor attachment to protein.
515–516	no effect on function in gpi-anchor attachment to protein.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-162791	Attachment of GPI anchor to uPAR	curated
R-HSA-392499	Metabolism of proteins	—
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 276 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, chr17q11, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_PROTEIN_MATURATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, KEGG_GLYCOSYLPHOSPHATIDYLINOSITOL_GPI_ANCHOR_BIOSYNTHESIS, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS

GO Biological Process (3): GPI anchor biosynthetic process (GO:0006506), attachment of GPI anchor to protein (GO:0016255), GPI anchored protein biosynthesis (GO:0180046)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), GPI-anchor transamidase complex (GO:0042765)

Reactome top-level categories

3 top-level categories:

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

GO top-level categories

15 GO namespaces:

Category	Terms
GPI anchored protein biosynthesis	2
protein maturation	2
GPI anchor metabolic process	1
glycolipid biosynthetic process	1
glycerophospholipid biosynthetic process	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
endoplasmic reticulum membrane	1
caspase complex	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 7 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
GPI anchored protein biosynthesis	BP	direct assay
attachment of GPI anchor to protein	BP	direct assay
GPI-anchor transamidase complex	CC	direct assay
membrane	CC	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 484 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIGS	GPAA1	O43292	910
PIGS	PIGT	Q969N2	892
PIGS	PIGK	Q92643	890
PIGS	PIGU	Q9H490	639
PIGS	PIGV	Q9NUD9	614
PIGS	PIGO	Q8TEQ8	521
PIGS	PIGM	Q9H3S5	520
PIGS	PIGB	Q92521	506
PIGS	PIGC	Q92535	462
PIGS	TMEM223	A0PJW6	442
PIGS	EAF2	Q96CJ1	429
PIGS	PIGP	P57054	408
PIGS	PGAP1	Q75T13	406
PIGS	PIGQ	Q9BRB3	404
PIGS	PIGW	Q7Z7B1	388

IntAct

Human interaction partners of PIGS in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

19 partners by confidence:

Partner	Interaction type	MIscore	Records
PIGT	physical association	0.770	2
GPAA1	association	0.760	6
PIGK	association	0.690	1
KRT40	physical association	0.560	3
KRTAP1-3	physical association	0.560	3
KRTAP10-8	physical association	0.560	3
KRTAP10-9	physical association	0.560	3
KRTAP19-2	physical association	0.560	3
KRTAP2-4	physical association	0.560	3
KRTAP6-3	physical association	0.560	3
KRTAP9-2	physical association	0.560	3
NOTCH2NLA	physical association	0.560	3
NOTCH2NLC	physical association	0.560	3
TRIP6	physical association	0.560	3
ACAP2	physical association	0.000	1
GPR89B	physical association	0.000	1
NDUFA9	physical association	0.000	1
NDUFS1	physical association	0.000	1
SOAT1	physical association	0.000	1

BioGRID (196 interactions; top human partners by supporting records): PIGT (Affinity Capture-MS; 4 records), PIGK (Affinity Capture-MS; 3 records), PRSS50 (Affinity Capture-MS; 3 records), FBXO6 (Affinity Capture-MS; 2 records), GPAA1 (Affinity Capture-MS; 2 records), LYPD3 (Affinity Capture-MS; 2 records), NOTCH2NL (Two-hybrid; 2 records), PIGU (Affinity Capture-MS; 2 records), VAPA (Proximity Label-MS; 2 records), VNN2 (Affinity Capture-MS; 2 records), ACAP2 (Affinity Capture-MS), AP1G2 (Affinity Capture-MS), AREL1 (Proximity Label-MS), ART4 (Affinity Capture-MS), ASPH (Affinity Capture-MS)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
PIGS	“up-regulates activity”	GPAA1	binding
PIGS	“up-regulates activity”	PIGK	binding

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
GAA1-GPI8-PIGT-PIG-PIGS complex	5	PIGS, PIGT, PIGU, GPAA1, PIGK

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 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
Keratinization	8	27.9×	2e-09

Disease & clinical

Genetic variants

Variant evidence for PIGS: 164 ClinVar records (16 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	8
Uncertain significance	90
Likely benign	38
Benign	4

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 16 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1119957	NM_033198.4(PIGS):c.734G>A (p.Trp245Ter)	Pathogenic	criteria provided, single submitter	2
3769036	NM_033198.4(PIGS):c.662_663del (p.Leu221fs)	Pathogenic	criteria provided, single submitter	1
585253	NM_033198.4(PIGS):c.108G>A (p.Trp36Ter)	Likely pathogenic	criteria provided, single submitter	2
585254	NM_033198.4(PIGS):c.101T>C (p.Leu34Pro)	Likely pathogenic	criteria provided, single submitter	2
2683019	NM_033198.4(PIGS):c.398del (p.Glu133fs)	Likely pathogenic	criteria provided, single submitter	1
3338277	NM_033198.4(PIGS):c.1436T>A (p.Leu479Ter)	Likely pathogenic	criteria provided, single submitter	1
4850817	NM_033198.4(PIGS):c.993del (p.Ala332fs)	Likely pathogenic	criteria provided, single submitter	1
4934335	NM_033198.4(PIGS):c.1392+1G>A	Likely pathogenic	criteria provided, single submitter	1
4934336	NM_033198.4(PIGS):c.1081-2A>T	Likely pathogenic	criteria provided, single submitter	1
4934343	NM_033198.4(PIGS):c.288C>G (p.Tyr96Ter)	Likely pathogenic	criteria provided, single submitter	1
585255	NM_033198.4(PIGS):c.1316_1352delinsGGTTGCT (p.Thr439_Lys451delinsArgLeuLeu)	Pathogenic	no assertion criteria provided	1
585257	NM_033198.4(PIGS):c.468+1G>C	Pathogenic	no assertion criteria provided	1
1119953	NM_033198.4(PIGS):c.174G>C (p.Gln58His)	Pathogenic	no assertion criteria provided	1
1119954	NM_033198.4(PIGS):c.1070G>A (p.Gly357Asp)	Pathogenic	no assertion criteria provided	1
1119955	NM_033198.4(PIGS):c.986C>G (p.Pro329Arg)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore PIGS’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 845):

Position(s)	Effect	Δscore	Sites
17:28554496–28554497	acceptor_loss	1.0000	4
17:28554849–28554850	donor_loss	1.0000	4
17:28558591–28558592	acceptor_loss	1.0000	5
17:28560047–28560048	donor_loss	1.0000	5
17:28560192–28560193	acceptor_loss	1.0000	4
17:28571047–28571048	donor_loss	1.0000	5
17:28554497	acceptor_loss	0.9900
17:28554850	donor_loss	0.9900
17:28555062–28555063	acceptor_loss	0.9900	6
17:28556114	donor_gain	0.9900

AlphaMissense

1,097 missense substitutions predicted likely pathogenic (of 3,586 scored), across 320 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F513	8	0.985	0.999
F526	8	0.968	0.992
F502	8	0.967	0.997
D516	8	0.963	0.990
F351	8	0.960	0.996
F324	8	0.895	0.994
F389	8	0.892	0.978
F231	8	0.888	0.993
D424	8	0.879	0.951
H509	8	0.692	0.837
W356	7	0.982	0.997
W245	7	0.964	0.994
F503	7	0.950	0.993
Q517	7	0.942	0.991
W421	7	0.940	0.990
F519	7	0.931	0.985
W35	7	0.906	0.994
E308	7	0.879	0.953
S232	7	0.875	0.997
N363	7	0.875	0.972

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	8.25e-05

Disease associations

OMIM: gene MIM:610271 | disease phenotypes: MIM:618143

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
glycosylphosphatidylinositol biosynthesis defect 18	Strong	Autosomal recessive	4

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
glycosylphosphatidylinositol biosynthesis defect 18	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
Congenital disorders of glycosylation	green
DDG2P	green
Fetal anomalies	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Early onset or syndromic epilepsy	amber
Paediatric disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (1): glycosylphosphatidylinositol biosynthesis defect 18 (MONDO:0029140)

HPO phenotypes

showing 60 of 64 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000158	Macroglossia
HP:0000212	Gingival overgrowth
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000331	Short chin
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000384	Preauricular skin tag
HP:0000391	Thickened helices
HP:0000476	Cystic hygroma
HP:0000505	Visual impairment
HP:0000639	Nystagmus
HP:0000687	Widely spaced teeth
HP:0000729	Autistic behavior
HP:0000748	Inappropriate laughter
HP:0000768	Pectus carinatum
HP:0000954	Single transverse palmar crease
HP:0001156	Brachydactyly
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001344	Absent speech
HP:0001382	Joint hypermobility
HP:0001537	Umbilical hernia
HP:0001640	Cardiomegaly
HP:0001989	Fetal akinesia sequence
HP:0002002	Deep philtrum
HP:0002019	Constipation
HP:0002059	Cerebral atrophy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002120	Cerebral cortical atrophy
HP:0002133	Status epilepticus
HP:0002188	Delayed CNS myelination
HP:0002240	Hepatomegaly
HP:0002540	Inability to walk
HP:0002553	Highly arched eyebrow
HP:0002650	Scoliosis
HP:0002804	Arthrogryposis multiplex congenita
HP:0002828	Multiple joint contractures
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003189	Long nose
HP:0003282	Decreased circulating alkaline phosphatase activity
HP:0003593	Infantile onset
HP:0004209	Clinodactyly of the 5th finger
HP:0004689	Short fourth metatarsal
HP:0006855	Cerebellar vermis atrophy
HP:0007359	Focal-onset seizure
HP:0009882	Short distal phalanx of finger
HP:0010044	Short 4th metacarpal
HP:0010851	EEG with burst suppression
HP:0011221	Vertical forehead creases
HP:0011344	Severe global developmental delay
HP:0011927	Short digit
HP:0011968	Feeding difficulties

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067379 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.53	Kd	29.79	nM	CHEMBL3752910
7.53	ED50	29.79	nM	CHEMBL3752910
6.59	Kd	254.7	nM	CHEMBL5653589
6.59	ED50	254.7	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149006: Binding affinity to human PIGS incubated for 45 mins by Kinobead based pull down assay	kd	0.0298	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149006: Binding affinity to human PIGS incubated for 45 mins by Kinobead based pull down assay	kd	0.2547	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	4
bisphenol A	affects cotreatment, increases methylation, increases expression	3
sodium arsenite	decreases expression, affects binding, increases reaction	2
Silicon Dioxide	decreases expression, decreases methylation	2
sodium arsenate	increases expression	1
titanium dioxide	decreases methylation	1
butyraldehyde	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Catechin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Vanadates	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	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
CHEMBL5652048	Binding	Binding affinity to human PIGS 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*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PIGS across ~30M SureChEMBL compounds — explore on Sugi Predict.