A4GALT

Summary

A4GALT (alpha 1,4-galactosyltransferase (P1PK blood group), HGNC:18149) is a protein-coding gene on chromosome 22q13.2, encoding Lactosylceramide 4-alpha-galactosyltransferase (Q9NPC4). Glycosyltransferase involved in biosynthesis of P1, P(k) and the rare NOR antigens of P1PK histo-blood group system.

The protein encoded by this gene catalyzes the transfer of galactose to lactosylceramide to form globotriaosylceramide, which has been identified as the P(k) antigen of the P blood group system. This protein, a type II membrane protein found in the Golgi, is also required for the synthesis of the bacterial verotoxins receptor. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 53947 — RefSeq curated summary.

At a glance

• Gene–disease (curated): A4GALT-congenital disorder of glycosylation (Definitive, ClinGen)
• GWAS associations: 25
• Clinical variants (ClinVar): 168 total — 21 pathogenic
• Phenotypes (HPO): 2
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_017436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18149
Approved symbol	A4GALT
Name	alpha 1,4-galactosyltransferase (P1PK blood group)
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	A14GALT, Gb3S, P(k)
Ensembl gene	ENSG00000128274
Ensembl biotype	protein_coding
OMIM	607922
Entrez	53947

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 52 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000249005, ENST00000381278, ENST00000401850, ENST00000465765, ENST00000483026, ENST00000642412, ENST00000647439, ENST00000868257, ENST00000868258, ENST00000868259, ENST00000868260, ENST00000868261, ENST00000868262, ENST00000868263, ENST00000868264, ENST00000868265, ENST00000868266, ENST00000868267, ENST00000868268, ENST00000868269, ENST00000868270, ENST00000868271, ENST00000868272, ENST00000868273, ENST00000868274, ENST00000868275, ENST00000868276, ENST00000868277, ENST00000868278, ENST00000868279, ENST00000868280, ENST00000868281, ENST00000912638, ENST00000959693, ENST00000959694, ENST00000959695, ENST00000959696, ENST00000959697, ENST00000959698, ENST00000959699, ENST00000959700, ENST00000959701, ENST00000959702, ENST00000959703, ENST00000959704, ENST00000959705, ENST00000959706, ENST00000959707, ENST00000959708, ENST00000959709, ENST00000959710, ENST00000959711, ENST00000959712, ENST00000959713, ENST00000959714

RefSeq mRNA: 2 — MANE Select: NM_017436 NM_001318038, NM_017436

CCDS: CCDS14041

Canonical transcript exons

ENST00000642412 — 3 exons

Exon	Start	End
ENSE00001488045	42692121	42693997
ENSE00003820895	42720797	42720870
ENSE00003825309	42695491	42695631

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 96.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.2962 / max 114.9046, expressed in 1338 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194470	4.3368	1191
194469	3.7569	1130
194468	0.2025	98

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	96.87	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.45	gold quality
right atrium auricular region	UBERON:0006631	94.53	gold quality
mucosa of stomach	UBERON:0001199	93.88	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.86	gold quality
lower esophagus	UBERON:0013473	93.83	gold quality
tibial nerve	UBERON:0001323	93.73	gold quality
heart left ventricle	UBERON:0002084	93.56	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.09	gold quality
cardiac ventricle	UBERON:0002082	93.00	gold quality
metanephros cortex	UBERON:0010533	92.58	gold quality
cardiac atrium	UBERON:0002081	92.34	gold quality
thoracic aorta	UBERON:0001515	92.06	gold quality
ascending aorta	UBERON:0001496	92.05	gold quality
popliteal artery	UBERON:0002250	91.86	gold quality
tibial artery	UBERON:0007610	91.85	gold quality
aorta	UBERON:0000947	91.83	gold quality
left uterine tube	UBERON:0001303	91.83	gold quality
endocervix	UBERON:0000458	91.76	gold quality
left coronary artery	UBERON:0001626	91.71	gold quality
heart	UBERON:0000948	91.54	gold quality
descending thoracic aorta	UBERON:0002345	91.25	gold quality
minor salivary gland	UBERON:0001830	91.20	gold quality
right coronary artery	UBERON:0001625	91.16	gold quality
lower esophagus mucosa	UBERON:0035834	90.80	gold quality
coronary artery	UBERON:0001621	90.78	gold quality
sural nerve	UBERON:0015488	90.68	gold quality
esophagus	UBERON:0001043	90.57	gold quality
omental fat pad	UBERON:0010414	89.66	gold quality
peritoneum	UBERON:0002358	89.62	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	120.60
E-MTAB-6819	yes	99.16
E-CURD-114	yes	73.57
E-ANND-3	yes	9.46
E-MTAB-7303	no	54.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

18 targeting A4GALT, 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-6778-3P	99.96	67.29	2693
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-3189-5P	97.55	66.71	655
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-4767	86.06	61.02	43
HSA-MIR-5587-3P	82.90	60.79	138

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 33)

• expression in megakaryoblastic leukemia cells (PMID:11782470)
• The P blood group phenotype is due to several disctint nonfunctional alleles of A4GALT without any predominant allele. (PMID:11896312)
• results strongly suggested that P1 synthase is identical to Gb3/CD77 synthase (PMID:12888565)
• Data show that a novel A4GALT missense mutation causes the p phenotype in Amish individuals. (PMID:18067504)
• the transcriptional regulation of the Gb3S gene by Sp1 might affect the verotoxin sensitivity of endothelial cell and Hemolytic uremic syndrome progression. (PMID:18757779)
• P(k) expression strongly influences susceptibility to HIV-1 infection, which implicates P(k) as a new endogenous cell-surface factor that may provide protection against HIV-1 infection. (PMID:19139081)
• These data show that globotriaosylceramide (Gb3) content, which is regulated by the expression of Gb3 synthase, determines the sensitivity of HeLa cells toward Shiga toxin. (PMID:19470247)
• We established by quantitative real-time PCR that both fresh colonic epithelial sections and HCT-8 cells express Gb3 synthase mRNA and the alternate Shiga toxin receptor globotetraosylceramide. (PMID:20732996)
• Data showed that GRINA-C was associated with Gb3 synthase, and may demonstrate a new type of posttranscriptional regulation of glycosyltransferases. (PMID:20837469)
• Increased globotriaosylceramide levels are detected in a transgenic mouse expressing human alpha1,4-galactosyltransferase in a mouse model for treating Fabry disease. (PMID:20961863)
• of A4GALT mRNA in cultured human bone marrow cells revealed novel transcripts containing only the noncoding exon 1 and a sequence (here termed exon 2a) from intron 1. (PMID:20971946)
• 2 Taiwanese individuals with p phenotype were homozygous for a & 428. No expression of P(k) & no enzyme activity were observed in cells transfected with the mutant construct. (PMID:21092013)
• Total urinary protein isoforms of globotriaosylceramide were used to identify Fabry disease in women. (PMID:21186071)
• Results suggest that the C631G mutation alters the acceptor specificity of Gb3/CD77 synthase, rendering it able to catalyze synthesis of the Gal(alpha1-4)Gal and Gal(alpha1-4)GalNAc moieties. (PMID:22965229)
• several P1PK-null alleles were identified. (PMID:23927681)
• P1-decorated PSGL-1/mIgG2b bound with high avidity to both Stx1 and Stx2, and as such constitutes a potential therapeutic inhibitor of these toxins. (PMID:24082034)
• these data elucidate a new explanation underlying the p phenotype, implicating the deleted regions of A4GALT as crucial for P1 and P(k) synthesis, possibly due to loss of binding sites for erythroid transcription factors. (PMID:24417201)
• The results of this investigation demonstrate a consistent association of A4GALT SNPs rs2143918 and rs5751348 with the P1/P2 phenotypes and suggest that SNP rs5751348 may lead to allelic variations in A4GALT gene expression (PMID:25041587)
• Mutation in the A4GALT gene is associated with rare p phenotype in P1Pk blood group system. (PMID:25863098)
• This is the first direct biochemical evidence that Gb3/CD77 synthase is able to synthesize two different glycosphingolipid antigens: P(k) and P1, and when p.Q211E substitution is present, the NOR antigen is also synthesized. (PMID:26773500)
• amino acid residue at position 211 of Gb3/CD77 synthase is critical for specificity and activity of the enzyme involved in formation of P(k), P1 and NOR antigens. Altogether, this approach affords a new insight into the mechanism of action of the human Gb3/CD77 synthase. (PMID:27538840)
• Study reports a novel mutation in the A4GALT gene that was responsible for a p phenotype in a Chinese individual. (PMID:27612185)
• The differential binding of transcription factor early growth response 1 to the SNP rs5751348 genomic region with the different genotypes in the A4GALT gene leads to differential activation of P(1) -A4GALT and P(2) -A4GALT expression. (PMID:29399809)
• These data indicate that RUNX1 regulates A4GALT and thereby the expression of clinically important glycosphingolipids implicated in blood group incompatibility and host-pathogen interactions. (PMID:29438961)
• A4GALT SNPs spur extra products of the human Gb3/CD77 synthase and underlie the P1PK blood group system (PMID:29709005)
• After serological and molecular biology tests on the patient and her family members, we confirmed that the patient and her sister possessed p phenotype, and the habitual abortion that occurred in the patient was caused by the anti-PP1Pk antibody. The p phenotype is a rare phenotype in P1Pk blood system, individuals with p phenotype lack all of the antigens of the P1Pk blood system and possess anti-PP1Pk antibody in their (PMID:31374005)
• The interaction between flagellin and the glycosphingolipid Gb3 on host cells contributes to Bacillus cereus acute infection. (PMID:32507026)
• Two Thai Burmese descendants with A4GALT*01N.21, p phenotype, and anti-PP1Pk. (PMID:32667820)
• Blood group P1 prediction using multiplex PCR genotyping of A4GALT among Thai blood donors. (PMID:33314439)
• Human Gb3/CD77 synthase produces P1 glycotope-capped N-glycans, which mediate Shiga toxin 1 but not Shiga toxin 2 cell entry. (PMID:33460651)
• Missing the sweet spot: one of the two N-glycans on human Gb3/CD77 synthase is expendable. (PMID:33978735)
• Identification of a novel P1PK allele (A4GALT*c.1-504_1044del1548) in two Chinese sisters with a history of recurrent spontaneous abortion. (PMID:35929100)
• Identification of a novel A4GALT*299A allele associated with the rare p phenotype in one Chinese family. (PMID:38501748)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	A4galt	ENSMUSG00000047878
rattus_norvegicus	A4galt	ENSRNOG00000009736
drosophila_melanogaster	alpha4GT1	FBGN0031491
drosophila_melanogaster	alpha4GT2	FBGN0039378
caenorhabditis_elegans		WBGENE00015309

Paralogs (1): A4GNT (ENSG00000118017)

Protein

Protein identifiers

Lactosylceramide 4-alpha-galactosyltransferase — Q9NPC4 (reviewed: Q9NPC4)

Alternative names: Alpha-1,4-N-acetylglucosaminyltransferase, Alpha-1,4-galactosyltransferase, Alpha4Gal-T1, CD77 synthase, Globotriaosylceramide synthase, P1/Pk synthase, UDP-galactose:beta-D-galactosyl-beta1-R 4-alpha-D-galactosyltransferase

All UniProt accessions (2): Q9NPC4, A0A0S2Z5J1

UniProt curated annotations — full annotation on UniProt →

Function. Glycosyltransferase involved in biosynthesis of P1, P(k) and the rare NOR antigens of P1PK histo-blood group system. Catalyzes the transfer of galactose from UDP-alpha-D-galactose in an alpha1,4 linkage to lactosylceramide/beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1<->1)-ceramide(d18:1(4E)) to produce globotriaosylceramide/globoside Gb3Cer (d18:1(4E)), also known as P(k) antigen or CD77. Globoside Gb3Cer/P(k)/CD77 is a root structure in biosynthesis pathway of neutral glycosphingolipids of the globo-series. Broadly expressed in cell membranes of immune cells and other tissues, Gb3Cer/P(k)/CD77 antigen may participate in mechanisms that regulate cell-cell interactions and cell differentiation. In germinal center B cells, Gb3Cer/CD77 interacts with CD19 to drive centroblast-to-centrocyte transition, B cell receptor complex assembly and T follicular helper cell differentiation. In epithelium, Gb3Cer regulates CDH1/E-cadherin-dependent cell-cell adhesion counteracting epithelial-to-mesenchymal transition. Synthesizes P1 glycan epitope (alpha-D-Gal-(1->4)-beta-D-Gal-(1->4)-GlcNAc-R) by transferring a galactose moiety to paragloboside nLc4 or to complex-type N-glycans. Generates the rare NOR1 and NOR2 antigens which carry a Gal(alpha1->4)GalNAc terminal moiety and are both derived from Gb4Cer precursor. Also able to transfer galactose to galactosylceramide/beta-D-Gal-(1<->1’)-Cer. (Microbial infection) P1 and Pk antigens are targeted by Shiga toxins (also called verotoxins), as a way to enter the cell, inhibit protein synthesis and induce apoptosis.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Ubiquitous. Highly expressed in kidney, heart, spleen, liver, testis and placenta.

Domain organisation. The conserved DXD motif is required for catalytic activity.

Pathway. Glycolipid biosynthesis. Protein modification; protein glycosylation.

Polymorphism. Genetic variation in A4GALT is responsible for the P1PK system blood group phenotypes [MIM:111400]. Different combinations or absence of the P blood group system antigens define 5 different phenotypes: P1, P2, P1(k), P2(k), and p. Genetic variation in A4GALT determines the p phenotype, which is rare and does not express any antigens. It is also known as null phenotype; p individuals have antibodies against P, P1 and P(k) antigens in their sera. These antibodies are clinically important because they can cause severe transfusion reactions and miscarriage. Genetic variation in A4GALT is also responsible for the NOR polyagglutination syndrome [MIM:111400]. Polyagglutination is the occurrence of red cell agglutination by virtually all human sera, but not by autologous serum or sera from newborns, creating a risk of complications during transfusions of NOR erythrocytes. It is caused by the unusual Gal(alpha1-4)GalNAc glycolipid epitope.

Similarity. Belongs to the glycosyltransferase 32 family.

RefSeq proteins (2): NP_001304967, NP_059132* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007577	GlycoTrfase_DXD_sugar-bd_CS	Conserved_site
IPR007652	A1-4-GlycosylTfrase_dom	Domain
IPR029044	Nucleotide-diphossugar_trans	Homologous_superfamily
IPR051981	A4GCT	Family

Pfam: PF04488, PF04572

Enzyme classification (BRENDA):

• EC 2.4.1.228 — lactosylceramide 4-alpha-galactosyltransferase (BRENDA: 4 organisms, 29 substrates, 5 inhibitors, 7 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
LACTOSYLCERAMIDE	0.0013–0.445	4
UDP-GALACTOSE	0.03–0.52	3

Catalyzed reactions (Rhea), 5 shown:

• a beta-D-Gal-(1->4)-beta-D-Glc-(1<->1)-Cer(d18:1(4E)) + UDP-alpha-D-galactose = a globoside Gb3Cer (d18:1(4E)) + UDP + H(+) (RHEA:11924)
• a globoside Gb4Cer + UDP-alpha-D-galactose = a globoside NOR1 + UDP + H(+) (RHEA:56184)
• a beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1<->1)-ceramide + UDP-alpha-D-galactose = a globoside Gb3Cer + UDP + H(+) (RHEA:56572)
• a beta-D-Gal-(1<->1’)-ceramide + UDP-alpha-D-galactose = alpha-D-Gal-(1->4)-beta-D-Gal-(1<->1’)-Cer + UDP + H(+) (RHEA:60044)
• an N(4)-{beta-D-Gal-(1->4)-beta-D-GlcNAc-(1->2)-alpha-D-Man-(1->3)-[beta-D-Gal-(1->4)-beta-D-GlcNAc-(1->2)-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc}-L-asparaginyl-[protein] + 2 UDP-alpha-D-galactose = an N(4)-{alpha-D-Gal-(1->4)-beta-D-Gal-(1->4)-beta-D-GlcNAc-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Gal-(1->4)-beta-D-Gal-(1->4)-beta-D-GlcNAc-(1->2)-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-beta-D-GlcNAc}-L-asparaginyl-[protein] + 2 UDP + 2 H(+) (RHEA:84931)

UniProt features (15 total): sequence variant 7, topological domain 2, glycosylation site 2, chain 1, mutagenesis site 1, transmembrane region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPC4-F1	89.54	0.73

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 (2): 121, 203

Mutagenesis-validated functional residues (1):

Position	Phenotype
194	abolishes gb3cer/p(k) and p1 antigen expression.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9840309	Glycosphingolipid biosynthesis
R-HSA-1430728	Metabolism
R-HSA-1660662	Glycosphingolipid metabolism
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 108 (showing top): GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, RICKMAN_METASTASIS_DN, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, KEGG_GLYCOSPHINGOLIPID_BIOSYNTHESIS_GLOBO_SERIES, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_GLYCOSPHINGOLIPID_BIOSYNTHETIC_PROCESS, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, REACTOME_SPHINGOLIPID_METABOLISM, GOBP_SPHINGOLIPID_BIOSYNTHETIC_PROCESS, GOBP_MEMBRANE_ORGANIZATION, GOBP_LIPOSACCHARIDE_METABOLIC_PROCESS

GO Biological Process (4): globoside biosynthetic process (GO:0001576), glycosphingolipid biosynthetic process (GO:0006688), plasma membrane organization (GO:0007009), lipid metabolic process (GO:0006629)

GO Molecular Function (6): galactosyltransferase activity (GO:0008378), toxic substance binding (GO:0015643), lactosylceramide 4-alpha-galactosyltransferase activity (GO:0050512), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), hexosyltransferase activity (GO:0016758)

GO Cellular Component (3): Golgi membrane (GO:0000139), membrane (GO:0016020), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Glycosphingolipid metabolism	1
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
globoside metabolic process	1
glycosphingolipid biosynthetic process	1
glycosphingolipid metabolic process	1
glycolipid biosynthetic process	1
sphingolipid biosynthetic process	1
endomembrane system organization	1
membrane organization	1
primary metabolic process	1
hexosyltransferase activity	1
binding	1
UDP-galactosyltransferase activity	1
catalytic activity	1
transferase activity	1
glycosyltransferase activity	1
Golgi apparatus	1
bounding membrane of organelle	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

784 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
A4GALT	B3GALNT1	O75752	969
A4GALT	B3GALT4	O96024	866
A4GALT	B3GALT1	Q9Y5Z6	833
A4GALT	B3GALT2	O43825	799
A4GALT	GABBR2	O75899	718
A4GALT	UGCG	Q16739	709
A4GALT	B4GALT6	Q9UBX8	705
A4GALT	B4GALT5	O43286	658
A4GALT	B3GNT5	Q9BYG0	612
A4GALT	ST8SIA2	Q92186	609
A4GALT	STX2	P32856	607
A4GALT	A3GALT2	U3KPV4	592
A4GALT	ITGA2B	P08514	560
A4GALT	ST3GAL2	Q16842	541
A4GALT	B3GALT5	Q9Y2C3	522

IntAct

8 interactions, top by confidence:

A	B	Type	Score
A4GALT	CANX	psi-mi:“MI:0914”(association)	0.530
SLC39A9	HPCAL1	psi-mi:“MI:0914”(association)	0.530
A4GALT	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
CFTR	A4GALT	psi-mi:“MI:0915”(physical association)	0.370
A4GALT	VPS37C	psi-mi:“MI:0914”(association)	0.350
A4GALT	CLGN	psi-mi:“MI:0914”(association)	0.350
rab40c.S	A4GALT	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (22): ABHD14A (Affinity Capture-MS), PTGFRN (Affinity Capture-MS), ICK (Affinity Capture-MS), FCGRT (Affinity Capture-MS), ABHD17B (Affinity Capture-MS), ICK (Affinity Capture-MS), ABHD14A (Affinity Capture-MS), ABHD17B (Affinity Capture-MS), CANX (Affinity Capture-MS), CANX (Affinity Capture-MS), ABHD17B (Affinity Capture-MS), VPS37C (Affinity Capture-MS), ABHD14A (Affinity Capture-MS), ICK (Affinity Capture-MS), CLGN (Affinity Capture-MS)

ESM2 similar proteins: A4IG53, A5PJK1, B1WC86, D2I2M6, F1N2K1, O95479, P58242, P70665, P82450, P98192, Q05AK6, Q08BG1, Q0P5H1, Q1JPD2, Q1LWG4, Q4V7R2, Q53F39, Q5R748, Q5RET5, Q5RFU0, Q5ZK82, Q61139, Q640M6, Q641Z7, Q658P3, Q6L5F5, Q6UX53, Q6ZT21, Q7G7C7, Q80XL7, Q8BMD6, Q8C7K6, Q8NBM8, Q8R2R1, Q8WTR4, Q92485, Q95KC9, Q99PR0, Q9D0Z3, Q9ES71

Diamond homologs: Q10323, Q14BT6, Q67BJ4, Q9JI93, Q9N289, Q9N290, Q9N291, Q9NPC4, Q9UNA3, P0C8Q4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	0
Uncertain significance	99
Likely benign	27
Benign	10

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1330161	GRCh37/hg19 22q13.2-13.33(chr22:42321321-51244066)x1	Pathogenic
145111	GRCh38/hg38 22q13.1-13.33(chr22:40202014-50735806)x3	Pathogenic
146215	GRCh38/hg38 22q13.2-13.31(chr22:42197923-47305564)x4	Pathogenic
147775	GRCh38/hg38 22q13.2-13.33(chr22:41871143-50739836)x1	Pathogenic
1526738	GRCh37/hg19 22q13.2-13.33(chr22:42972719-51197838)	Pathogenic
1704313	GRCh37/hg19 22q13.2(chr22:43103054-43207442)x1	Pathogenic
2425394	NC_000022.10:g.(?42456283)(43089957_?)del	Pathogenic
253509	GRCh37/hg19 22q11.1-13.33(chr22:16054691-51237518)x3	Pathogenic
253617	GRCh37/hg19 22q12.3-13.33(chr22:35728929-51220961)x3	Pathogenic
39437	NM_017436.7(A4GALT):c.631C>G (p.Gln211Glu)	Pathogenic
395140	GRCh37/hg19 22q11.1-13.33(chr22:16054691-51237463)x3	Pathogenic
441574	GRCh37/hg19 22q13.2-13.33(chr22:42441918-51197838)x1	Pathogenic
443581	GRCh37/hg19 22q13.2-13.33(chr22:43050743-51197838)x1	Pathogenic
565053	GRCh37/hg19 22q13.2-13.33(chr22:43111156-51183840)x1	Pathogenic
565054	GRCh37/hg19 22q13.2-13.33(chr22:42955616-51183840)x1	Pathogenic
57636	GRCh38/hg38 22q13.2-13.33(chr22:42433752-50738932)x1	Pathogenic
57945	GRCh38/hg38 22q13.2-13.33(chr22:42653747-50739836)x3	Pathogenic
688285	GRCh37/hg19 22q13.2(chr22:43059474-43145703)x1	Pathogenic
816216	GRCh37/hg19 22q12.2-13.33(chr22:30654764-51197838)x3	Pathogenic
816565	GRCh37/hg19 22q13.1-13.33(chr22:40502364-51197838)x3	Pathogenic
983188	GRCh37/hg19 22q11.1-13.33(chr22:16197005-51224252)x3	Pathogenic

SpliceAI

155 predictions. Top by Δscore:

Variant	Effect	Δscore
22:42693998:C:CC	acceptor_gain	0.8900
22:42693993:CTGGT:C	acceptor_gain	0.8800
22:42694845:A:AC	donor_gain	0.8200
22:42694846:C:CC	donor_gain	0.8200
22:42694846:CTGG:C	donor_gain	0.8200
22:42694857:T:TA	donor_gain	0.8000
22:42694601:T:A	donor_gain	0.7700
22:42693994:TGGT:T	acceptor_gain	0.7200
22:42694842:A:C	donor_gain	0.7200
22:42694749:G:C	donor_gain	0.6700
22:42694541:A:AC	donor_gain	0.6600
22:42694542:C:CC	donor_gain	0.6600
22:42693997:TC:T	acceptor_loss	0.6500
22:42693999:TG:T	acceptor_loss	0.6500
22:42694000:G:C	acceptor_loss	0.6500
22:42694001:CAAGA:C	acceptor_loss	0.6400
22:42694007:A:C	acceptor_loss	0.6400
22:42694588:TTAG:T	donor_gain	0.6400
22:42694002:AAGA:A	acceptor_loss	0.6200
22:42694003:AGAGA:A	acceptor_loss	0.5900
22:42694004:GAGAT:G	acceptor_loss	0.5800
22:42694012:C:CT	acceptor_loss	0.5800
22:42694005:A:C	acceptor_loss	0.5700
22:42694021:T:TC	acceptor_loss	0.5700
22:42694022:C:CC	acceptor_loss	0.5700
22:42694753:CGGAG:C	donor_gain	0.5700
22:42693995:GGT:G	acceptor_gain	0.5600
22:42694006:GATGA:G	acceptor_loss	0.5600
22:42694023:A:C	acceptor_loss	0.5600
22:42694019:CATCA:C	acceptor_loss	0.5500

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000044878 (22:42699680 C>T), RS1000075701 (22:42703486 C>A,G), RS1000182225 (22:42699456 G>A,T), RS1000201351 (22:42693300 C>G,T), RS1000256376 (22:42710314 C>G,T), RS1000512348 (22:42715726 TA>T,TAA), RS1000540522 (22:42709933 T>C), RS1000657744 (22:42719989 C>T), RS1000672218 (22:42699102 T>A), RS1000695903 (22:42714693 C>A,G), RS1000813115 (22:42714508 G>A,C), RS1000861453 (22:42702097 G>A,C), RS1000862006 (22:42708582 G>A), RS1000946448 (22:42720188 A>C), RS1001049559 (22:42715517 C>G)

Disease associations

OMIM: gene MIM:607922 | disease phenotypes: MIM:606232, MIM:114000

GenCC curated gene-disease

Disease	Classification	Inheritance
A4GALT-congenital disorder of glycosylation	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
A4GALT-congenital disorder of glycosylation	Definitive	AR

Mondo (3): Phelan-McDermid syndrome (MONDO:0011652), Caffey disease (MONDO:0007244), A4GALT-congenital disorder of glycosylation (MONDO:0100587)

Orphanet (2): Phelan-McDermid syndrome (Orphanet:48652), Caffey disease (Orphanet:1310)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0010970	Blood group antigen abnormality

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST003831_16	Asthma	5.000000e-06
GCST004523_3	Resting metabolic rate	2.000000e-06
GCST004599_221	Mean platelet volume	1.000000e-12
GCST004601_208	Red blood cell count	3.000000e-23
GCST004604_5	Hematocrit	4.000000e-14
GCST004615_139	Hemoglobin concentration	7.000000e-18
GCST004616_177	Platelet distribution width	9.000000e-26
GCST006011_3	Mean corpuscular volume	2.000000e-08
GCST006585_1423	Blood protein levels	2.000000e-15
GCST008058_176	Estimated glomerular filtration rate	9.000000e-34
GCST008059_139	Estimated glomerular filtration rate	6.000000e-29
GCST008745_33	Estimated glomerular filtration rate in non-diabetics	4.000000e-12
GCST008747_153	Estimated glomerular filtration rate	2.000000e-17
GCST008747_35	Estimated glomerular filtration rate	3.000000e-12
GCST009698_54	Metabolite levels	1.000000e-08
GCST009698_55	Metabolite levels	1.000000e-23
GCST010083_279	Hemoglobin levels	2.000000e-31
GCST010242_247	HDL cholesterol levels	1.000000e-08
GCST012020_61	Serum metabolite levels	1.000000e-26
GCST90002383_111	Hematocrit	2.000000e-30
GCST90002384_507	Hemoglobin	1.000000e-36
GCST90002395_622	Mean platelet volume	4.000000e-33
GCST90002397_610	Mean spheric corpuscular volume	1.000000e-16
GCST90002400_512	Plateletcrit	1.000000e-19
GCST90002403_706	Red blood cell count	2.000000e-52

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0008004	resting metabolic rate measurement
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007984	platelet component distribution width
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007985	platelet crit

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006958	Hyperostosis, Cortical, Congenital	C05.116.099.708.479; C05.116.540.400; C16.614.465
C536801	Telomeric 22q13 Monosomy Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, decreases reaction, affects methylation	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
sodium arsenite	affects methylation, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Smoke	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
chlorophyllin	decreases reaction, increases expression	1
terbufos	increases methylation	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
Scutellaria barbata extract	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Carbofuran	affects response to substance	1
Curcumin	decreases reaction, increases expression	1
Fonofos	increases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Thiram	decreases expression	1
Triclosan	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C3QY	CMCi006-A-1	Induced pluripotent stem cell	Male
CVCL_D9X0	Ubigene HeLa A4GALT KO	Cancer cell line	Female
CVCL_U968	HML-Gb3	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07281079	PHASE3	RECRUITING	A Study of NNZ-2591 in Pediatric Participants With Phelan-McDermid Syndrome
NCT07593391	PHASE3	RECRUITING	An Open-label Study of NNZ-2591 in Pediatric Participants With Phelan-McDermid Syndrome
NCT01525901	PHASE2	COMPLETED	Clinical Trial in 22q13 Deletion Syndrome(Phelan-McDermid Syndrome)
NCT02710084	PHASE2	COMPLETED	Piloting Treatment With Intranasal Oxytocin in Phelan-McDermid Syndrome
NCT03493607	PHASE2	COMPLETED	AMO-01 to Treat Adolescents and Adults With Phelan-McDermid Syndrome (PMS) and Co-morbid Epilepsy
NCT04003207	PHASE2	COMPLETED	Growth Hormone Treatment in Children With Phelan McDermid Syndrome
NCT05025241	PHASE2	COMPLETED	An Open-Label Study of Oral NNZ-2591 in Phelan-McDermid Syndrome (PMS-001)
NCT05187377	PHASE2	COMPLETED	A Controlled Trial of Growth Hormone in Phelan-McDermid Syndrome and Idiopathic Autism
NCT05105685	PHASE1/PHASE2	COMPLETED	Effectiveness of Recombinant Human Growth Hormone Therapy for Children With PMS
NCT06662188	PHASE1/PHASE2	RECRUITING	JAG201 Gene Therapy Study in Children & Adults With SHANK3 Haploinsufficiency
NCT02000167	Not specified	COMPLETED	Mitochondrial Dysfunction in Phelan-McDermid Syndrome
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT03426059	Not specified	COMPLETED	Mapping the Phenotype in Adults With Phelan-McDermid Syndrome
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04312152	Not specified	UNKNOWN	Q10 Ubiquinol in Autism Spectrum Disorder and in Phelan-McDermid Syndrome.
NCT07014020	Not specified	RECRUITING	RB001 Gene Therapy Study in Children With SHANK3-related Phelan McDermid Syndrome (PMS)