ALG6

Summary

ALG6 (ALG6 alpha-1,3-glucosyltransferase, HGNC:23157) is a protein-coding gene on chromosome 1p31.3, encoding Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (Q9Y672). Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation. It is a selective cancer dependency (DepMap: 12.2% of cell lines).

This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. Mutations in this gene are associated with congenital disorders of glycosylation type Ic.

Source: NCBI Gene 29929 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ALG6-congenital disorder of glycosylation 1C (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 894 total — 52 pathogenic, 73 likely-pathogenic
• Phenotypes (HPO): 42
• Cancer dependency (DepMap): dependent in 12.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_013339

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23157
Approved symbol	ALG6
Name	ALG6 alpha-1,3-glucosyltransferase
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000088035
Ensembl biotype	protein_coding
OMIM	604566
Entrez	29929

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 6 protein_coding, 6 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000263440, ENST00000462390, ENST00000465969, ENST00000487136, ENST00000494765, ENST00000603108, ENST00000647818, ENST00000648964, ENST00000649570, ENST00000650331, ENST00000650469, ENST00000650494, ENST00000920026, ENST00000948329, ENST00000948330, ENST00000948331, ENST00000948332

RefSeq mRNA: 1 — MANE Select: NM_013339 NM_013339

CCDS: CCDS30735

Canonical transcript exons

ENST00000263440 — 15 exons

Exon	Start	End
ENSE00000773307	63411926	63412061
ENSE00000956721	63414061	63414146
ENSE00001011179	63436823	63438553
ENSE00001600322	63411146	63411331
ENSE00001600530	63402254	63402343
ENSE00001691995	63407062	63407126
ENSE00001701791	63406317	63406399
ENSE00001719718	63404453	63404541
ENSE00002308325	63370771	63371059
ENSE00003464925	63428733	63428801
ENSE00003495118	63419370	63419440
ENSE00003645879	63428928	63429126
ENSE00003674883	63415873	63415957
ENSE00003681045	63396513	63396597
ENSE00003841041	63367627	63367687

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 91.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.9814 / max 108.5483, expressed in 1745 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3172	9.7340	1743
3171	0.2474	79

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	91.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.22	gold quality
upper leg skin	UBERON:0004262	87.39	gold quality
mononuclear cell	CL:0000842	87.27	gold quality
monocyte	CL:0000576	87.26	gold quality
leukocyte	CL:0000738	87.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.55	gold quality
esophagus squamous epithelium	UBERON:0006920	86.38	gold quality
granulocyte	CL:0000094	86.13	gold quality
ileal mucosa	UBERON:0000331	86.13	gold quality
adrenal tissue	UBERON:0018303	85.48	gold quality
mucosa of transverse colon	UBERON:0004991	85.36	gold quality
rectum	UBERON:0001052	85.26	gold quality
tibial nerve	UBERON:0001323	85.23	gold quality
lower esophagus mucosa	UBERON:0035834	85.20	gold quality
skin of hip	UBERON:0001554	84.83	gold quality
skin of abdomen	UBERON:0001416	84.62	gold quality
epithelium of nasopharynx	UBERON:0001951	84.04	gold quality
nasopharynx	UBERON:0001728	84.03	gold quality
pigmented layer of retina	UBERON:0001782	83.97	gold quality
esophagus mucosa	UBERON:0002469	83.97	gold quality
spleen	UBERON:0002106	83.75	gold quality
skin of leg	UBERON:0001511	83.74	gold quality
zone of skin	UBERON:0000014	83.59	gold quality
right uterine tube	UBERON:0001302	83.37	gold quality
lymph node	UBERON:0000029	83.27	gold quality
epithelium of esophagus	UBERON:0001976	83.13	gold quality
body of pancreas	UBERON:0001150	83.11	gold quality
oral cavity	UBERON:0000167	83.04	gold quality
jejunal mucosa	UBERON:0000399	83.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

102 targeting ALG6, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 12.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. (PMID:11875054)
• Our findings extend the causes of CDG to larger DNA deletions and identify the first Japanese CDG-Ic mutation. (PMID:16321363)
• Five novel base substitutions in the hALG6 gene were also found: three in exon 5 (c.383T>C, c.390G>A, and c.429G>C) and two in a downstream intervening sequence (IVS5+17C/T and IVS5+34G/A). (PMID:21899441)
• ALG6-CDG has been now described in 89 patients. (PMID:27287710)
• Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) initially diagnosed as ALG6-CDG: Functional evidence for benignity of the ALG6 c.391T>C (p.Tyr131His) variant and further expanding the BBSOAS phenotype. (PMID:32407885)
• Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation-Effect of an ALG6 Modifier Variant. (PMID:38256083)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	alg6	ENSDARG00000017617
mus_musculus	Alg6	ENSMUSG00000073792
rattus_norvegicus	Alg6	ENSRNOG00000009045
drosophila_melanogaster	gny	FBGN0032234
caenorhabditis_elegans		WBGENE00007435

Paralogs (1): ALG8 (ENSG00000159063)

Protein

Protein identifiers

Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase — Q9Y672 (reviewed: Q9Y672)

Alternative names: Asparagine-linked glycosylation protein 6 homolog, Dol-P-Glc:Man(9)GlcNAc(2)-PP-Dol alpha-1,3-glucosyltransferase, Dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase

All UniProt accessions (7): Q9Y672, A0A3B3IS62, A0A3B3ITD6, A0A3B3ITI5, A0A3B3ITL6, R4GMS5, S4R350

UniProt curated annotations — full annotation on UniProt →

Function. Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation. The assembly of dolichol-linked oligosaccharides begins on the cytosolic side of the endoplasmic reticulum membrane and finishes in its lumen. The sequential addition of sugars to dolichol pyrophosphate produces dolichol-linked oligosaccharides containing fourteen sugars, including two GlcNAcs, nine mannoses and three glucoses. Once assembled, the oligosaccharide is transferred from the lipid to nascent proteins by oligosaccharyltransferases. In the lumen of the endoplasmic reticulum, adds the first glucose residue from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide intermediate Man(9)GlcNAc(2)-PP-Dol to produce Glc(1)Man(9)GlcNAc(2)-PP-Dol. Glc(1)Man(9)GlcNAc(2)-PP-Dol is a substrate for ALG8, the following enzyme in the biosynthetic pathway.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Congenital disorder of glycosylation 1C (CDG1C) [MIM:603147] A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the ALG6/ALG8 glucosyltransferase family.

RefSeq proteins (1): NP_037471* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004856	Glyco_trans_ALG6/ALG8	Family

Pfam: PF03155

Enzyme classification (BRENDA):

• EC 2.4.1.267 — dolichyl-P-Glc:Man9GlcNAc2-PP-dolichol alpha-1,3-glucosyltransferase (BRENDA: 4 organisms, 2 substrates, 1 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• an alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + a di-trans,poly-cis-dolichyl beta-D-glucosyl phosphate = an alpha-D-Glc-(1->3)-alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->2)-alpha-D-Man-(1->6)]-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + a di-trans,poly-cis-dolichyl phosphate + H(+) (RHEA:30635)

UniProt features (39 total): topological domain 12, transmembrane region 11, sequence variant 10, sequence conflict 4, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y672-F1	93.08	0.83

Functional residue map

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

Glycosylation sites (1): 59

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-446193	Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
R-HSA-4724289	Defective ALG6 causes CDG-1c
R-HSA-1643685	Disease
R-HSA-3781860	Diseases associated with N-glycosylation of proteins
R-HSA-3781865	Diseases of glycosylation
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 218 (showing top): CREL_01, SHEPARD_BMYB_MORPHOLINO_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MYOGENIN_Q6, MODULE_255, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, KEGG_N_GLYCAN_BIOSYNTHESIS, MODULE_317, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, NFKB_C, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GGGNNTTTCC_NFKB_Q6_01, MYOD_Q6, SLEBOS_HEAD_AND_NECK_CANCER_WITH_HPV_UP

GO Biological Process (3): protein N-linked glycosylation (GO:0006487), dolichol-linked oligosaccharide biosynthetic process (GO:0006488), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (7): dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity (GO:0004583), dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity (GO:0042281), glucosyltransferase activity (GO:0046527), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), hexosyltransferase activity (GO:0016758)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), lumenal side of endoplasmic reticulum membrane (GO:0098553), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Asparagine N-linked glycosylation	1
Diseases associated with N-glycosylation of proteins	1
Diseases of glycosylation	1
Diseases of metabolism	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glycoprotein biosynthetic process	1
protein N-linked glycosylation	1
carbohydrate derivative biosynthetic process	1
glucosyltransferase activity	1
dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity	1
dolichol-linked oligosaccharide biosynthetic process	1
hexosyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
glycosyltransferase activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
endoplasmic reticulum membrane	1
lumenal side of membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

890 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALG6	ALG1	Q9BT22	964
ALG6	PMM2	O15305	908
ALG6	ALG12	Q9BV10	899
ALG6	ALG3	Q92685	873
ALG6	ALG5	Q9Y673	854
ALG6	ALG2	Q9H553	834
ALG6	ALG11	Q2TAA5	795
ALG6	DPAGT1	Q9H3H5	793
ALG6	DPM1	O60762	770
ALG6	PDCD6	O75340	763
ALG6	PLTP	P55058	749
ALG6	ALG13	Q9NP73	744
ALG6	MPDU1	O75352	742
ALG6	ALG14	Q96F25	729
ALG6	SRD5A3	Q9H8P0	723

IntAct

22 interactions, top by confidence:

A	B	Type	Score
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
ALG6	ALG8	psi-mi:“MI:0915”(physical association)	0.500
sseJ	NPC1	psi-mi:“MI:0914”(association)	0.460
ACBD3	PDCD6	psi-mi:“MI:0914”(association)	0.350
ACBD3	BCKDHB	psi-mi:“MI:0914”(association)	0.350
ADGRE5	TMEM223	psi-mi:“MI:0914”(association)	0.350
DPEP1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
M	DENND11	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
CRELD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
ALG6	FGFR3	psi-mi:“MI:0914”(association)	0.350
KRAS	IGKV2D-29	psi-mi:“MI:0914”(association)	0.350
TCTN3	TMEM120B	psi-mi:“MI:2364”(proximity)	0.270
IMMP2L	MRPL45	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (53): ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Proximity Label-MS), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Positive Genetic), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS), ALG6 (Affinity Capture-MS)

ESM2 similar proteins: A6X919, A8MR93, A8Y3M2, D4AD75, O43053, O80505, O82244, P34413, P47088, P54002, Q0P5D9, Q23361, Q2PZI1, Q2UB20, Q3T1L5, Q3TAE8, Q4IJT0, Q4R4E1, Q4V7R2, Q500W7, Q5EA10, Q5NVS8, Q5RAH7, Q5RCJ4, Q66IJ4, Q6CRE7, Q6FXQ5, Q6P8H8, Q6ZPD9, Q71B07, Q7RXP5, Q7SXZ1, Q802T2, Q8C2R7, Q8CHJ0, Q8CHJ1, Q8K358, Q8L638, Q8VDB2, Q94A15

Diamond homologs: O43053, Q09226, Q10479, Q12001, Q2UB20, Q3T1L5, Q3TAE8, Q54QG6, Q5NVS8, Q6P8H8, Q7RXP5, Q802T2, Q9BVK2, Q9FF17, Q9VKX7, Q9Y672, Q0P5D9, O80505, P40351, P52887, Q1DJR8, Q2HA14, Q4IJT0, Q554E2, Q5AJD2, Q5AWM9, Q6BRE5, Q6CJR2, Q6FKM3, Q759R3, Q9W3V8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	73
Uncertain significance	266
Likely benign	381
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076049	NM_013339.4(ALG6):c.409G>T (p.Glu137Ter)	Pathogenic
1370628	NM_013339.4(ALG6):c.1326+1G>T	Pathogenic
1405663	NM_013339.4(ALG6):c.171T>G (p.Tyr57Ter)	Pathogenic
1411147	NM_013339.4(ALG6):c.723del (p.Phe242fs)	Pathogenic
1414979	NM_013339.4(ALG6):c.835del (p.Trp279fs)	Pathogenic
1415838	NM_013339.4(ALG6):c.1171_1172del (p.Val391fs)	Pathogenic
1421154	NC_000001.10:g.(?63867905)(63902691_?)del	Pathogenic
1431177	NM_013339.4(ALG6):c.574del (p.Ala192fs)	Pathogenic
1450530	NM_013339.4(ALG6):c.791del (p.Phe264fs)	Pathogenic
1453538	NM_013339.4(ALG6):c.484_485insA (p.Gly162fs)	Pathogenic
1456351	NC_000001.10:g.(?63836649)(63836750_?)del	Pathogenic
1456612	NM_013339.4(ALG6):c.254_255del (p.Tyr85fs)	Pathogenic
1457700	NM_013339.4(ALG6):c.510del (p.Gly172fs)	Pathogenic
1457885	NM_013339.4(ALG6):c.121C>T (p.Gln41Ter)	Pathogenic
1458787	NC_000001.10:g.(?63885021)(63885131_?)del	Pathogenic
1460456	NM_013339.4(ALG6):c.634del (p.Cys212fs)	Pathogenic
2004426	NM_013339.4(ALG6):c.493C>T (p.Gln165Ter)	Pathogenic
2029354	NM_013339.4(ALG6):c.1029dup (p.His344fs)	Pathogenic
2167373	NM_013339.4(ALG6):c.889C>T (p.Gln297Ter)	Pathogenic
2190114	NM_013339.4(ALG6):c.399T>A (p.Cys133Ter)	Pathogenic
2425852	NC_000001.10:g.(?63836639)(63902701_?)del	Pathogenic
2729920	NM_013339.4(ALG6):c.168G>A (p.Trp56Ter)	Pathogenic
2735137	NM_013339.4(ALG6):c.642del (p.Leu214fs)	Pathogenic
2747566	NM_013339.4(ALG6):c.527G>A (p.Trp176Ter)	Pathogenic
2748650	NM_013339.4(ALG6):c.147del (p.Phe49fs)	Pathogenic
2752249	NM_013339.4(ALG6):c.974_984del (p.Phe325fs)	Pathogenic
2755130	NM_013339.4(ALG6):c.737G>A (p.Trp246Ter)	Pathogenic
2760855	NM_013339.4(ALG6):c.1308del (p.Arg437fs)	Pathogenic
2772318	NM_013339.4(ALG6):c.352del (p.Ile118fs)	Pathogenic
2799271	NM_013339.4(ALG6):c.281G>A (p.Trp94Ter)	Pathogenic

SpliceAI

1968 predictions. Top by Δscore:

Variant	Effect	Δscore
1:63370902:G:GT	donor_gain	1.0000
1:63370926:G:GG	donor_gain	1.0000
1:63402339:TATGT:T	donor_gain	1.0000
1:63402340:ATGT:A	donor_gain	1.0000
1:63402342:GT:G	donor_gain	1.0000
1:63402344:G:GG	donor_gain	1.0000
1:63406315:A:AG	acceptor_gain	1.0000
1:63406316:G:GA	acceptor_gain	1.0000
1:63428926:A:AG	acceptor_gain	1.0000
1:63428927:G:GA	acceptor_gain	1.0000
1:63428927:GT:G	acceptor_gain	1.0000
1:63428927:GTAT:G	acceptor_gain	1.0000
1:63429018:A:AG	acceptor_gain	1.0000
1:63429078:G:GT	donor_gain	1.0000
1:63436821:A:AG	acceptor_gain	1.0000
1:63436822:G:GG	acceptor_gain	1.0000
1:63367683:GCGGG:G	donor_gain	0.9900
1:63367685:GGG:G	donor_gain	0.9900
1:63367686:GG:G	donor_gain	0.9900
1:63367686:GGG:G	donor_gain	0.9900
1:63367687:GG:G	donor_gain	0.9900
1:63367688:G:GG	donor_gain	0.9900
1:63367689:T:A	donor_loss	0.9900
1:63367813:G:T	donor_gain	0.9900
1:63370872:G:GT	donor_gain	0.9900
1:63391324:C:G	donor_gain	0.9900
1:63396563:C:T	donor_gain	0.9900
1:63396593:CAATG:C	donor_loss	0.9900
1:63396594:AATGG:A	donor_loss	0.9900
1:63396595:ATGG:A	donor_loss	0.9900

AlphaMissense

3325 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:63411250:A:T	K200I	0.999
1:63411251:A:C	K200N	0.999
1:63411251:A:T	K200N	0.999
1:63419419:A:T	K346I	0.999
1:63396540:A:T	D37V	0.998
1:63396560:T:A	W44R	0.998
1:63396560:T:C	W44R	0.998
1:63407122:T:C	F164L	0.998
1:63407124:T:A	F164L	0.998
1:63407124:T:G	F164L	0.998
1:63411159:A:C	S170R	0.998
1:63411161:T:A	S170R	0.998
1:63411161:T:G	S170R	0.998
1:63396539:G:C	D37H	0.997
1:63396540:A:C	D37A	0.997
1:63396540:A:G	D37G	0.997
1:63396555:G:C	R42T	0.997
1:63396556:A:C	R42S	0.997
1:63396556:A:T	R42S	0.997
1:63396562:G:C	W44C	0.997
1:63396562:G:T	W44C	0.997
1:63402288:T:A	W68R	0.997
1:63402288:T:C	W68R	0.997
1:63419416:A:T	E345V	0.997
1:63419418:A:C	K346Q	0.997
1:63419420:A:C	K346N	0.997
1:63419420:A:T	K346N	0.997
1:63396541:T:A	D37E	0.996
1:63396541:T:G	D37E	0.996
1:63396596:T:A	W56R	0.996

dbSNP variants (sampled 300 via entrez): RS1000066522 (1:63394916 A>G), RS1000079468 (1:63438243 T>C), RS1000193072 (1:63405829 T>C), RS1000249654 (1:63398649 G>A), RS1000264387 (1:63409118 T>C), RS1000282818 (1:63438569 G>A), RS1000307160 (1:63395026 C>G,T), RS1000341636 (1:63385035 A>C), RS1000356040 (1:63413217 T>C), RS1000417510 (1:63366451 T>C), RS1000612492 (1:63374623 G>A), RS1000616212 (1:63389317 C>A), RS1000654382 (1:63423354 A>G), RS1000689631 (1:63389760 A>C,G), RS1000696684 (1:63409402 A>G,T)

Disease associations

OMIM: gene MIM:604566 | disease phenotypes: MIM:603147, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
ALG6-congenital disorder of glycosylation 1C	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
ALG6-congenital disorder of glycosylation 1C	Definitive	AR
cystic kidney disease	Limited	AD

Mondo (3): ALG6-congenital disorder of glycosylation 1C (MONDO:0011291), craniosynostosis (MONDO:0015469), cystic kidney disease (MONDO:0002473)

Orphanet (2): ALG6-CDG (Orphanet:79320), Craniosynostosis (Orphanet:1531)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000486	Strabismus
HP:0000510	Rod-cone dystrophy
HP:0000546	Retinal degeneration
HP:0000707	Abnormality of the nervous system
HP:0000924	Abnormality of the skeletal system
HP:0000952	Jaundice
HP:0001156	Brachydactyly
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001284	Areflexia
HP:0001321	Cerebellar hypoplasia
HP:0001392	Abnormality of the liver
HP:0001508	Failure to thrive
HP:0001929	Reduced factor XI activity
HP:0001976	Reduced antithrombin III activity
HP:0001999	Abnormal facial shape
HP:0002243	Protein-losing enteropathy
HP:0002625	Deep venous thrombosis
HP:0002650	Scoliosis
HP:0002652	Skeletal dysplasia
HP:0003073	Hypoalbuminemia
HP:0003256	Abnormality of the coagulation cascade
HP:0003563	Decreased LDL cholesterol concentration
HP:0003621	Juvenile onset

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008529_36	Tea consumption	9.000000e-06
GCST90002396_134	Mean reticulocyte volume	1.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010091	tea consumption measurement
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D052177	Kidney Diseases, Cystic	C12.050.351.968.419.403; C12.200.777.419.403; C12.950.419.403
C535741	Congenital disorder of glycosylation type 1C (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
tianma gouteng yin	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Leflunomide	decreases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Bile Acids and Salts	increases expression	1
Cadmium	increases abundance, increases expression	1
Cannabidiol	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Quercetin	decreases expression	1
Thiram	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DB08	GM20949	Finite cell line	Female
CVCL_SC28	HAP1 ALG6 (-) 1	Cancer cell line	Male
CVCL_SC29	HAP1 ALG6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT04705051	PHASE3	TERMINATED	Long-term Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) With Venglustat
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT02684435	PHASE2	COMPLETED	Contrast-enhanced Ultrasound of the Kidney
NCT03196076	PHASE2	COMPLETED	Contrast-enhanced Ultrasound for Complex Kidney Lesion Diagnosis in Patients With CKD Extension
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis
NCT02371551	Not specified	COMPLETED	Evaluation of Complex Renal Cyst With CEUS/Functional MRI Versus CT
NCT04670887	Not specified	NOT_YET_RECRUITING	Comparison of Surgery and Active Surveillance in the Treatment of Bosniak III Renal Cysts
NCT05286632	Not specified	COMPLETED	KidneYou - Innovative Digital Therapy