ALG9

protein-coding

ALG9 alpha-1,2-mannosyltransferase, the group of Dolichyl D-mannosyl phosphate dependent mannosyltransferases

Gene summary

This gene encodes an alpha-1,2-mannosyltransferase enzyme that functions in lipid-linked oligosaccharide assembly. Mutations in this gene result in congenital disorder of glycosylation type Il. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

Previous symbols:

DIBD1

MANE transcript

NM_024740.2

Inheritance

AR, AD

ClinVar variants

P:45U:126B:77

Top phenotype

Congenital disorder of glycosylation, type Il

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr11:111,782,195-111,871,581

External References & Databases

Ensembl (ENSG00000086848)

Transcript & Mutation Effects

hg38 • Region Span ~89.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ALG9-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012117

Submitter: Labcorp Genetics (formerly Invitae)

ALG9-congenital disorder of glycosylationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012117

Submitter: Ambry Genetics

ALG9-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012117

Submitter: G2P

Gillessen-Kaesbach-Nishimura syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009890

Submitter: Ambry Genetics

ALG9-associated autosomal dominant polycystic kidney diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700000

Submitter: ClinGen

The *ALG9* gene is located 11q23.1 and encodes an alpha-1,2-mannosyltransferase. The enzyme is involved in N-linked glycosylation and catalyzes two mannose transfers onto lipid-linked oligosaccharide (PMID: 25966638). Monoallelic *ALG9* pathogenic variants were first reported in relation to autosomal dominant polycystic kidney disease (ADPKD) in 2019 (Besse et al., PMID: 31395617). Of note, biallelic ALG9 pathogenic variants have been associated with the congenital disorder of glycosylation, type 1L (CDG-1L; OMIM #6087776) and Gillessen-Kaesbach-Nishimura syndrome (GIKANIS; OMIM #263210). Given that ALG9-associated ADPKD and ALG9-associated CDG-1L have different inheritance modes and phenotypic manifestations, we have split the two disease entities. Here, we only curate the association between *ALG9* and ADPKD (http://purl.obolibrary.org/obo/MONDO_0700000). ADPKD-ALG9 patients are characterized by the presence of renal cysts, however, these patients show variable penetrance and expressivity. For instance, Besse et al., 2019 demonstrate that 7/14 of the probands with available abdominal imaging had clear evidence of multicystic kidney disease (multiple kidney cysts, bilaterally), whereas the remaining 7 probands had less than 4 renal cysts (n=4), no imaging data for analysis (n=3), or had reached ESRD by the time of renal imaging (n=1). This large variation of expressivity should be considered when evaluating ALG9 carriers. At least ten variants (4 nonsense, 3 frameshift, 1 canonical splice-site, and 2 missense) reported in 2 publications have been included in this curation (PMID: 31395617; 37761895). The presumed mechanism of pathogenicity based on published evidence is loss of function whereby variants in the ALG9 gene leads to impaired polycystin-1 maturation (PMID: 31395617). Evidence supporting this gene-disease relationship includes case-level genetic data. Variants in this gene have been reported in at least 19 individuals in 4 publications (PMID: 31395617; 32398770; 37761895; 36573973). Of these individuals, ten were reported to have clear evidence of cystic kidney disease; of the remaining nine, five were reported to not display multiple kidney cysts, three had insufficient clinical data available for assessment, and one harbored a benign variant. This is evidence consistent ADPKD-*ALG9* having variable penetrance and expressivity. For this gene-disease curation, only the ten probands who showed clear evidence of cystic kidney disease as well as putatively pathogenic *ALG9* variants were counted for case-level genetic evidence. A total of 12 pts. for genetic evidence was reached. In summary, there is “Definitive” evidence to support this gene-disease relationship and no convincing evidence has emerged that contradicts the relationship. This gene-disease pair was originally evaluated as ”Moderate” by the Kidney Cystic and Ciliopathy Disorders GCEP on 08/26/2020 (SOP Version 7). It was reevaluated on 09/11/2023 and the classification changed (SOP Version 9).

ALG9-associated autosomal dominant polycystic kidney diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700000

Submitter: PanelApp Australia

ALG9-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012117

Submitter: PanelApp Australia

autosomal dominant polycystic kidney diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: Genomics England PanelApp

ALG9-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012117

Submitter: Ambry Genetics

autosomal dominant polycystic kidney diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: Orphanet

ALG9-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012117

Submitter: Orphanet

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IlAR

Manifestation: Biochemical; Craniofacial; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Pulmonary; Renal

Intervention: Hematologic

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 15148656; 15945070; 19451548; 25966638

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG9 variants in ClinVar

14 Conditions Cataloged

ALG9 congenital disorder of glycosylationTotal: 231

Gillessen-Kaesbach-Nishimura syndromeTotal: 79

not providedTotal: 69

ALG9-related disorderTotal: 47

not specifiedTotal: 34

Inborn genetic diseasesTotal: 20

ALG9-associated autosomal dominant polycystic kidney diseaseTotal: 10

Autosomal dominant polycystic liver diseaseTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024740.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	60 clinvar	1 clinvar	67
missense	2 clinvar	2 clinvar	110 clinvar	13 clinvar	3 clinvar	130
nonsense	6 clinvar	10 clinvar	4 clinvar			20
start loss						0
frameshift	5 clinvar	9 clinvar				14
splice donor/acceptor (+/-2bp)		11 clinvar	6 clinvar			17
Total	13	32	126	73	4	248

Highest pathogenic variant AF is 0.0000712557

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024740.2	RefSeq	NP_079016.2	15	MANE Select
ENST00000616540.5	Ensembl	ENSP00000482437.1	15	MANE Select
NM_001077690.1	RefSeq	NP_001071158.1	15	Standard
NM_001077691.2	RefSeq	NP_001071159.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

N-Glycan biosynthesis - Homo sapiens (human)
Post-translational protein modification
Metabolism of proteins
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
Asparagine N-linked glycosylation

Biological Process

dolichol-linked oligosaccharide biosynthetic process
mannosylation

Molecular Function

alpha-1,2-mannosyltransferase activity
mannosyltransferase activity
dol-P-Man:Man(8)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity
dol-P-Man:Man(6)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000531154
Coding exons: 11
Length: 89387
Individuals with no LoFs: 124776
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 124796
p: 0.0000801

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.01	190	233	0.814	0.0000120	2901
Missense (PolyPhen)		64	89.251	0.71708		1112
Synonymous	0.366	81	85.3	0.950	0.00000433	863
Loss of Function	2.91	10	26.0	0.385	0.00000137	308

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000056	0.000056	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the transfer of mannose from Dol-P-Man to lipid-linked oligosaccharides. {ECO:0000269|PubMed:15148656, ECO:0000269|PubMed:15945070}.;
Disease: DISEASE: Congenital disorder of glycosylation 1L (CDG1L) [MIM:608776]: 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. {ECO:0000269|PubMed:15148656, ECO:0000269|PubMed:15945070}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Gillessen-Kaesbach-Nishimura syndrome (GIKANIS) [MIM:263210]: A rare autosomal recessive syndrome characterized by severe skeletal dysplasia, facial dysmorphic features, polycystic kidney disease and other visceral malformations. It may be lethal in utero or early in life. The skeletal features uniformly comprise a round pelvis, mesomelic shortening of the upper limbs and defective ossification of the cervical spine. {ECO:0000269|PubMed:25966638}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.216

Intolerance Scores

LoFtool: 0.881
RVIS EVS: 0.51
RVIS percentile EVS: 80.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.231

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium