GPAA1

Summary

GPAA1 (glycosylphosphatidylinositol anchor attachment 1, HGNC:4446) is a protein-coding gene on chromosome 8q24.3, encoding GPI-anchor transamidase component GPAA1 (O43292). 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.

Posttranslational glycosylphosphatidylinositol (GPI) anchor attachment serves as a general mechanism for linking proteins to the cell surface membrane. The protein encoded by this gene presumably functions in GPI anchoring at the GPI transfer step. The mRNA transcript is ubiquitously expressed in both fetal and adult tissues. The anchor attachment protein 1 contains an N-terminal signal sequence, 1 cAMP- and cGMP-dependent protein kinase phosphorylation site, 1 leucine zipper pattern, 2 potential N-glycosylation sites, and 8 putative transmembrane domains.

Source: NCBI Gene 8733 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycosylphosphatidylinositol biosynthesis defect 15 (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 646 total — 24 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_003801

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4446
Approved symbol	GPAA1
Name	glycosylphosphatidylinositol anchor attachment 1
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	GAA1, hGAA1
Ensembl gene	ENSG00000197858
Ensembl biotype	protein_coding
OMIM	603048
Entrez	8733

Gene structure

Transcript identifiers

Ensembl transcripts: 91 — 41 retained_intron, 35 protein_coding, 14 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000355091, ENST00000361036, ENST00000524418, ENST00000525087, ENST00000525308, ENST00000526341, ENST00000527144, ENST00000527653, ENST00000528073, ENST00000529503, ENST00000529638, ENST00000530258, ENST00000530633, ENST00000530796, ENST00000531593, ENST00000532758, ENST00000534072, ENST00000703441, ENST00000703620, ENST00000703621, ENST00000703622, ENST00000703623, ENST00000703631, ENST00000703632, ENST00000703633, ENST00000703634, ENST00000703635, ENST00000703647, ENST00000703648, ENST00000703649, ENST00000703650, ENST00000703651, ENST00000703652, ENST00000703653, ENST00000703654, ENST00000703670, ENST00000703671, ENST00000703672, ENST00000703673, ENST00000703674, ENST00000703675, ENST00000703676, ENST00000703677, ENST00000703678, ENST00000703679, ENST00000703680, ENST00000703681, ENST00000703682, ENST00000703720, ENST00000703721, ENST00000703722, ENST00000703723, ENST00000703724, ENST00000703725, ENST00000704789, ENST00000704790, ENST00000704791, ENST00000704793, ENST00000704794, ENST00000704795, ENST00000704796, ENST00000704797, ENST00000704798, ENST00000704799, ENST00000704806, ENST00000704807, ENST00000704808, ENST00000704809, ENST00000704810, ENST00000704811, ENST00000704812, ENST00000704813, ENST00000877763, ENST00000877764, ENST00000877765, ENST00000877766, ENST00000877767, ENST00000877768, ENST00000877769, ENST00000934431, ENST00000934432, ENST00000934433, ENST00000967422, ENST00000967423, ENST00000967424, ENST00000967425, ENST00000967426, ENST00000967427, ENST00000967428, ENST00000967429, ENST00000967430

RefSeq mRNA: 1 — MANE Select: NM_003801 NM_003801

CCDS: CCDS43776

Canonical transcript exons

ENST00000355091 — 12 exons

Exon	Start	End
ENSE00001309755	144085882	144086216
ENSE00001326703	144084722	144084875
ENSE00003474011	144084134	144084330
ENSE00003475052	144083939	144084040
ENSE00003545486	144084413	144084609
ENSE00003554193	144083714	144083861
ENSE00003608677	144085043	144085138
ENSE00003620589	144085573	144085743
ENSE00003624425	144085289	144085479
ENSE00003652962	144083124	144083303
ENSE00003661130	144083389	144083500
ENSE00003992493	144082634	144082804

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.3439 / max 183.8912, expressed in 1817 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91469	46.7016	1817
91470	0.4515	273
91471	0.1907	83

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	97.60	gold quality
right lobe of thyroid gland	UBERON:0001119	97.56	gold quality
apex of heart	UBERON:0002098	97.49	gold quality
left lobe of thyroid gland	UBERON:0001120	97.15	gold quality
right adrenal gland	UBERON:0001233	97.05	gold quality
left adrenal gland	UBERON:0001234	97.00	gold quality
right adrenal gland cortex	UBERON:0035827	96.99	gold quality
mucosa of transverse colon	UBERON:0004991	96.97	gold quality
left adrenal gland cortex	UBERON:0035825	96.96	gold quality
metanephros cortex	UBERON:0010533	96.95	gold quality
body of stomach	UBERON:0001161	96.81	gold quality
body of uterus	UBERON:0009853	96.81	gold quality
endocervix	UBERON:0000458	96.77	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.70	gold quality
left uterine tube	UBERON:0001303	96.68	gold quality
thyroid gland	UBERON:0002046	96.62	gold quality
right ovary	UBERON:0002118	96.57	gold quality
adrenal cortex	UBERON:0001235	96.52	gold quality
endometrium epithelium	UBERON:0004811	96.47	gold quality
right atrium auricular region	UBERON:0006631	96.41	gold quality
mucosa of stomach	UBERON:0001199	96.37	gold quality
thoracic aorta	UBERON:0001515	96.33	gold quality
right uterine tube	UBERON:0001302	96.30	gold quality
ascending aorta	UBERON:0001496	96.29	gold quality
left ovary	UBERON:0002119	96.24	gold quality
descending thoracic aorta	UBERON:0002345	96.22	gold quality
minor salivary gland	UBERON:0001830	96.21	gold quality
body of pancreas	UBERON:0001150	96.20	gold quality
right coronary artery	UBERON:0001625	96.20	gold quality
left coronary artery	UBERON:0001626	96.20	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MYC	Activation

Literature-anchored findings (GeneRIF, showing 11)

• a conserved proline in the last transmembrane segment of Gaa1 is required for glycosylphosphatidylinositol recognition by GPI transamidase (PMID:14660601)
• passively retained in the ER by a signalless mechanism (PMID:15713669)
• Increased expression of glycosyl-phosphatidylinositol anchor attachment protein 1 is associated with gene amplification in hepatocellular carcinoma (PMID:16642471)
• Results show an increased expression level and elevated copy number for GAA1 in head and neck squamous carcinoma, suggesting a role for this GPI anchor subunit in HNSCC. (PMID:18028549)
• the lumenal domain of GAA1/GPAA1 has a 3D structure similar to that of an M28-type aminopeptidase. GAA1/GPAA1 is a candidate for the enzyme that catalyzes the peptide bond formation between the omega-site and a phosphoethanolamine group of GPI lipid anchor. (PMID:24743167)
• The splicing mutation was found to decrease GPAA1 mRNA. (PMID:29100095)
• Mechanistically, GPAA1 enhanced the levels of metastasis-associated GPI-anchored proteins to increase tumour metastasis and intensified lipid raft formation, which consequently promoted the interaction between EGFR and ERBB2 as well as downstream pro-proliferative signalling. (PMID:31118109)
• GPAA1 promotes progression of childhood acute lymphoblastic leukemia through regulating c-myc. (PMID:32432756)
• A novel variant in GPAA1, encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes. (PMID:32533362)
• Structural modelling of the lumenal domain of human GPAA1, the metallo-peptide synthetase subunit of the transamidase complex, reveals zinc-binding mode and two flaps surrounding the active site. (PMID:32993792)
• Subunits of the GPI transamidase complex localize to the endoplasmic reticulum and nuclear envelope in Drosophila. (PMID:33496978)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpaa1	ENSDARG00000074571
mus_musculus	Gpaa1	ENSMUSG00000022561
rattus_norvegicus	Gpaa1	ENSRNOG00000029280
drosophila_melanogaster	GAA1	FBGN0029818
caenorhabditis_elegans	gpaa-1	WBGENE00018006

Protein

Protein identifiers

GPI-anchor transamidase component GPAA1 — O43292 (reviewed: O43292)

Alternative names: GAA1 protein homolog, Glycosylphosphatidylinositol anchor attachment 1 protein

All UniProt accessions (28): A0A994J3S1, A0A994J3S5, A0A994J3Y5, A0A994J3Y9, A0A994J3Z2, A0A994J4D0, A0A994J4E7, A0A994J4P7, A0A994J4Q3, A0A994J4X4, A0A994J4X7, A0A994J5C8, A0A994J5D7, A0A994J6H8, A0A994J6I4, A0A994J6I9, A0A994J6V5, A0A994J6W5, A0A994J6W8, A0A994J6X1, A0A994J7A1, A0A994J7N7, E9PLV6, E9PM11, E9PM94, E9PPZ9, E9PQ31, O43292

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. Binds GPI-anchor.

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

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitously expressed in fetal and adult tissues. Expressed at higher levels in fetal tissues than adult tissues.

Disease relevance. Glycosylphosphatidylinositol biosynthesis defect 15 (GPIBD15) [MIM:617810] An autosomal recessive disorder characterized by delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most patients, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor biosynthesis.

Isoforms (2)

UniProt ID	Names	Canonical?
O43292-1	1	yes
O43292-2	2

RefSeq proteins (1): NP_003792* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007246	Gaa1	Family

Pfam: PF04114

UniProt features (92 total): helix 25, strand 15, mutagenesis site 14, topological domain 8, transmembrane region 8, binding site 6, sequence variant 6, turn 5, initiator methionine 1, chain 1, glycosylation site 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7WLD	ELECTRON MICROSCOPY	2.53
8IMX	ELECTRON MICROSCOPY	2.85
7W72	ELECTRON MICROSCOPY	3.1
8IMY	ELECTRON MICROSCOPY	3.22

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43292-F1	87.48	0.63

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 (6): 49; 51; 354; 355; 355; 356

Disulfide bonds (1): 259–266

Glycosylation sites (1): 203

Mutagenesis-validated functional residues (14):

Position	Phenotype
52	no effect on function in gpi-anchor attachment to protein.
137	no effect on function in gpi-anchor attachment to protein.
153	no effect on function in gpi-anchor attachment to protein.
186–187	no effect on function in gpi-anchor attachment to protein.
188	no effect on function in gpi-anchor attachment to protein.
203	no effect on function in gpi-anchor attachment to protein.
226	no effect on function in gpi-anchor attachment to protein.
250	decreased function in gpi-anchor attachment to protein.
325	no effect on function in gpi-anchor attachment to protein.
328	no effect on function in gpi-anchor attachment to protein.
329	no effect on function in gpi-anchor attachment to protein.
351–352	no effect on function in gpi-anchor attachment to protein.
354	reduces gpi-anchor transamidase activity by ~25%.
517	no effect on function in gpi-anchor attachment to protein.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-162791	Attachment of GPI anchor to uPAR

MSigDB gene sets: 248 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, MORF_MTA1, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, MORF_UBE2I, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MORF_HDAC1, MORF_CDK2, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MORF_HDAC2, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS

GO Biological Process (4): GPI anchor biosynthetic process (GO:0006506), protein retention in ER lumen (GO:0006621), attachment of GPI anchor to protein (GO:0016255), GPI anchored protein biosynthesis (GO:0180046)

GO Molecular Function (3): GPI anchor binding (GO:0034235), GPI-anchor transamidase activity (GO:0003923), protein binding (GO:0005515)

GO Cellular Component (7): mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), centrosome (GO:0005813), cytosol (GO:0005829), membrane (GO:0016020), GPI-anchor transamidase complex (GO:0042765)

Reactome top-level categories

Rollup of top-1 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
GPI anchored protein biosynthesis	2
protein maturation	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
GPI anchor metabolic process	1
glycolipid biosynthetic process	1
glycerophospholipid biosynthetic process	1
maintenance of protein localization in endoplasmic reticulum	1
phospholipid binding	1
glycolipid binding	1
cysteine-type endopeptidase activity	1
transferase activity, transferring nitrogenous groups	1
binding	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
centriole	1
microtubule organizing center	1
endoplasmic reticulum membrane	1
caspase complex	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1

Protein interactions and networks

STRING

1004 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPAA1	PIGT	Q969N2	999
GPAA1	PIGK	Q92643	999
GPAA1	PIGS	Q96S52	914
GPAA1	PIGU	Q9H490	866
GPAA1	PIGO	Q8TEQ8	762
GPAA1	PIGL	Q9Y2B2	745
GPAA1	PIGB	Q92521	723
GPAA1	FXN	Q16595	720
GPAA1	PIGV	Q9NUD9	717
GPAA1	PIGH	Q14442	716
GPAA1	PIGP	P57054	716
GPAA1	PIGM	Q9H3S5	715
GPAA1	PIGW	Q7Z7B1	711
GPAA1	PIGC	Q92535	710
GPAA1	PIGZ	Q86VD9	681

IntAct

128 interactions, top by confidence:

A	B	Type	Score
PIGK	GPAA1	psi-mi:“MI:0914”(association)	0.860
GPAA1	PIGK	psi-mi:“MI:0914”(association)	0.860
PIGK	GPAA1	psi-mi:“MI:0915”(physical association)	0.860
PIGT	GPAA1	psi-mi:“MI:0914”(association)	0.790
GPAA1	PIGT	psi-mi:“MI:0914”(association)	0.790
GPAA1	PIGT	psi-mi:“MI:0915”(physical association)	0.790
PIGS	GPAA1	psi-mi:“MI:0914”(association)	0.760
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
MOXD1	GPAA1	psi-mi:“MI:0914”(association)	0.620

BioGRID (149): GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Proximity Label-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), GPAA1 (Affinity Capture-MS), PIGT (Affinity Capture-MS), GPAA1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A1A4Q9, A5YM72, A6NLP5, D3KCC4, I3L5V6, O43292, P10938, Q00973, Q05B52, Q09200, Q10468, Q14623, Q148G5, Q16586, Q2V8X7, Q3SZV0, Q561R2, Q5E9M9, Q5M868, Q5ZL13, Q66H45, Q69ZF3, Q6P3D0, Q6P7A1, Q6P9Z4, Q6SZW1, Q6TEC1, Q6ZPS2, Q7TMC8, Q864R5, Q86TX2, Q8IXI1, Q8N0W3, Q8N3Y3, Q8N6R0, Q8NF37, Q8NI29, Q8TCD5, Q8VBW8

Diamond homologs: O43292, P39012, Q9US48, Q9WTK3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GPAA1	“up-regulates quantity by expression”	MYC	“transcriptional regulation”
PIGS	“up-regulates activity”	GPAA1	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — BLCA.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	20
Uncertain significance	265
Likely benign	290
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028657	NM_003801.4(GPAA1):c.319_320del (p.Ser107fs)	Pathogenic
1457926	NM_003801.4(GPAA1):c.1007del (p.Gly336fs)	Pathogenic
1685859	NM_003801.4(GPAA1):c.1826C>T (p.Pro609Leu)	Pathogenic
1701557	NM_003801.4(GPAA1):c.956_966delinsG (p.Leu319fs)	Pathogenic
1805088	NM_003801.4(GPAA1):c.1465C>T (p.Gln489Ter)	Pathogenic
2005928	NM_003801.4(GPAA1):c.184G>T (p.Glu62Ter)	Pathogenic
2006619	NM_003801.4(GPAA1):c.1218del (p.Gly408fs)	Pathogenic
2074613	NM_003801.4(GPAA1):c.390C>G (p.Tyr130Ter)	Pathogenic
2084338	NM_003801.4(GPAA1):c.694dup (p.Val232fs)	Pathogenic
2110432	NM_003801.4(GPAA1):c.862C>T (p.Gln288Ter)	Pathogenic
2424759	NC_000008.10:g.(?145137634)(145138963_?)del	Pathogenic
2748353	NM_003801.4(GPAA1):c.1223del (p.Gly408fs)	Pathogenic
2779106	NM_003801.4(GPAA1):c.567del (p.Leu190fs)	Pathogenic
2871959	NM_003801.4(GPAA1):c.809del (p.Gly270fs)	Pathogenic
2889593	NM_003801.4(GPAA1):c.525T>G (p.Tyr175Ter)	Pathogenic
3389917	NM_003801.4(GPAA1):c.1484G>A (p.Trp495Ter)	Pathogenic
3618169	NM_003801.4(GPAA1):c.943G>T (p.Glu315Ter)	Pathogenic
3672465	NM_003801.4(GPAA1):c.187C>T (p.Gln63Ter)	Pathogenic
3722635	NM_003801.4(GPAA1):c.936C>G (p.Tyr312Ter)	Pathogenic
453248	NM_003801.4(GPAA1):c.981_993del (p.Gln327fs)	Pathogenic
453249	NM_003801.4(GPAA1):c.920del (p.Gly307fs)	Pathogenic
4700358	NM_003801.4(GPAA1):c.1179G>A (p.Trp393Ter)	Pathogenic
4810179	NM_003801.4(GPAA1):c.262_272del (p.Pro88fs)	Pathogenic
523980	NM_003801.4(GPAA1):c.619del (p.Met207fs)	Pathogenic
1324502	NM_003801.4(GPAA1):c.616+1G>T	Likely pathogenic
1335932	NM_003801.4(GPAA1):c.1258C>T (p.Gln420Ter)	Likely pathogenic
1394986	NM_003801.4(GPAA1):c.1165-1C>T	Likely pathogenic
1466783	NM_003801.4(GPAA1):c.814-1G>T	Likely pathogenic
1474766	NM_003801.4(GPAA1):c.616+1G>C	Likely pathogenic
1504691	NM_003801.4(GPAA1):c.515-2A>G	Likely pathogenic

SpliceAI

1774 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144083118:TCACA:T	acceptor_loss	1.0000
8:144083119:CACAG:C	acceptor_loss	1.0000
8:144083120:ACAG:A	acceptor_loss	1.0000
8:144083121:CA:C	acceptor_loss	1.0000
8:144083122:A:AC	acceptor_loss	1.0000
8:144083122:A:AG	acceptor_gain	1.0000
8:144083122:AGC:A	acceptor_gain	1.0000
8:144083122:AGCGT:A	acceptor_gain	1.0000
8:144083123:G:GT	acceptor_gain	1.0000
8:144083123:GC:G	acceptor_gain	1.0000
8:144083123:GCG:G	acceptor_gain	1.0000
8:144083123:GCGT:G	acceptor_gain	1.0000
8:144083123:GCGTG:G	acceptor_gain	1.0000
8:144083295:G:GT	donor_gain	1.0000
8:144083300:CGGGG:C	donor_loss	1.0000
8:144083301:GGG:G	donor_gain	1.0000
8:144083302:GG:G	donor_gain	1.0000
8:144083302:GGG:G	donor_gain	1.0000
8:144083303:GG:G	donor_gain	1.0000
8:144083303:GGTGA:G	donor_loss	1.0000
8:144083304:G:C	donor_loss	1.0000
8:144083304:G:GG	donor_gain	1.0000
8:144083305:T:A	donor_loss	1.0000
8:144083481:A:G	donor_gain	1.0000
8:144083494:GCGC:G	donor_gain	1.0000
8:144083496:GC:G	donor_gain	1.0000
8:144083497:C:CG	donor_gain	1.0000
8:144083497:C:G	donor_gain	1.0000
8:144083501:G:GG	donor_gain	1.0000
8:144083509:G:GT	donor_gain	1.0000

AlphaMissense

3915 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144083957:A:T	K178I	0.998
8:144083731:C:A	N128K	0.997
8:144083731:C:G	N128K	0.997
8:144084007:T:A	W195R	0.997
8:144084007:T:C	W195R	0.997
8:144083739:G:A	G131D	0.996
8:144083958:A:C	K178N	0.996
8:144083958:A:T	K178N	0.996
8:144083959:G:C	D179H	0.996
8:144083960:A:C	D179A	0.996
8:144083960:A:T	D179V	0.996
8:144083456:T:C	F108L	0.995
8:144083458:C:A	F108L	0.995
8:144083458:C:G	F108L	0.995
8:144083828:G:T	G161W	0.995
8:144083847:C:A	A167D	0.995
8:144083969:T:C	F182S	0.995
8:144084752:C:A	N347K	0.995
8:144084752:C:G	N347K	0.995
8:144083738:G:C	G131R	0.994
8:144083828:G:A	G161R	0.994
8:144083828:G:C	G161R	0.994
8:144083950:T:A	W176R	0.994
8:144083950:T:C	W176R	0.994
8:144083745:T:C	L133P	0.993
8:144084606:G:A	G336D	0.993
8:144084742:G:C	R344P	0.993
8:144084813:T:C	F368L	0.993
8:144084815:C:A	F368L	0.993
8:144084815:C:G	F368L	0.993

dbSNP variants (sampled 300 via entrez): RS1000244007 (8:144082089 C>G), RS1000296212 (8:144081819 T>G), RS1001959101 (8:144082716 C>G), RS1002623580 (8:144085305 C>T), RS1004321110 (8:144086671 T>C,G), RS1004652982 (8:144081141 T>G), RS1006341786 (8:144082448 C>T), RS1008677351 (8:144086018 C>T), RS1008770896 (8:144086362 G>A,T), RS1009738128 (8:144083310 G>C), RS1010330279 (8:144082416 T>A), RS1010633613 (8:144082099 C>T), RS1010907740 (8:144084471 T>A,C), RS1012491502 (8:144081798 G>T), RS1014307630 (8:144081452 C>T)

Disease associations

OMIM: gene MIM:603048 | disease phenotypes: MIM:617810

GenCC curated gene-disease

Disease	Classification	Inheritance
glycosylphosphatidylinositol biosynthesis defect 15	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
glycosylphosphatidylinositol biosynthesis defect 15	Definitive	AR

Mondo (1): glycosylphosphatidylinositol biosynthesis defect 15 (MONDO:0060627)

Orphanet (1): Neurodevelopmental delay-seizures-ophthalmic anomalies-osteopenia-cerebellar atrophy syndrome (Orphanet:529665)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000316	Hypertelorism
HP:0000341	Narrow forehead
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000505	Visual impairment
HP:0000545	Myopia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000657	Oculomotor apraxia
HP:0000750	Delayed speech and language development
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0001321	Cerebellar hypoplasia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0002066	Gait ataxia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006249_14	Serum metabolite levels	8.000000e-51
GCST008103_86	Bipolar disorder	1.000000e-06
GCST008115_8	Bipolar I disorder	2.000000e-08
GCST009798_65	Asthma	1.000000e-08
GCST012353_35	Serum metabolite concentrations in chronic kidney disease	2.000000e-22

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009963	bipolar I disorder

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067041 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.08	Kd	841.3	nM	CHEMBL5653589
6.08	ED50	841.3	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 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	2148453: Binding affinity to human GPAA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.8413	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression, increases methylation	4
sodium arsenite	decreases expression, increases expression	2
Cisplatin	increases expression, affects response to substance, affects cotreatment	2
Smoke	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
ferrous chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases expression	1
Catechin	decreases expression, affects cotreatment	1
Coumestrol	affects cotreatment, increases expression	1
Cycloheximide	increases expression, affects cotreatment	1
Hydralazine	decreases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Manganese	affects expression	1
Phenobarbital	affects expression	1
Piroxicam	increases expression, affects cotreatment	1
Quercetin	increases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	1
Thiram	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
CHEMBL5651495	Binding	Binding affinity to human GPAA1 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_B2Y2	Abcam HEK293T GPAA1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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