MAN2C1

protein-coding

mannosidase alpha class 2C member 1, the group of Mannosidases alpha class 2

Gene summary

Predicted to enable alpha-mannosidase activity. Predicted to be involved in oligosaccharide catabolic process. Predicted to be located in cytosol. Implicated in congenital disorder of deglycosylation 2. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

MANA1
MANA

MANE transcript

NM_006715.4

Inheritance

ClinVar variants

P:16U:243B:19

Top phenotype

Congenital disorder of deglycosylation 2

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr15:75,355,207-75,368,612

External References & Databases

Ensembl (ENSG00000140400)

Transcript & Mutation Effects

hg38 • Region Span ~13.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital disorder of deglycosylation 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030770

Submitter: ClinGen

MAN2C1 was first reported in relation to autosomal recessive congenital disorder of deglycosylation 2 in 2022 (Maia et al., PMID 35045343). Five variants (missense, frameshift, splice site) that have been reported in 4 probands in 1 publication (PMID 35045343) are included in this curation. Patients have a range of symptoms, including dysmorphic facies, impaired intellectual development, and brain anomalies. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. As there are specific splice site and LOF variants present in GnomAD in homozygous state (including c.2303G>A and c.601-2A>G and 15-75364145-GTGTAC-G) there is a possibility of reduced penetrance for this condition. This gene-disease relationship is also supported by in vitro assays showing a deficiency in free oligosaccharide processing (PMIDs 35045343, 16848760) as well as a mouse model (PMID 24550399). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Disorder of Glycosylation GCEP on the meeting date November 7, 2024 (SOP Version 10).

congenital disorder of deglycosylation 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030770

Submitter: G2P

congenital disorder of deglycosylation 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030770

Submitter: PanelApp Australia

congenital disorder of deglycosylation 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030770

Submitter: Illumina

congenital disorder of deglycosylation 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030770

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Congenital disorder of deglycosylation 2AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 35045343

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAN2C1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 223

Congenital disorder of deglycosylation 2Total: 32

not providedTotal: 18

MAN2C1-related disorderTotal: 8

Hypogonadotropic hypogonadism 27 without anosmiaTotal: 1

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006715.4. 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			4 clinvar	10 clinvar		14
missense		3 clinvar	226 clinvar	9 clinvar		238
nonsense		1 clinvar				1
start loss						0
frameshift		7 clinvar	1 clinvar			8
splice donor/acceptor (+/-2bp)		5 clinvar	12 clinvar			17
Total	0	16	243	19	0	278

Highest pathogenic variant AF is 0.0016981339

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 133 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006715.4	RefSeq	NP_006706.2	26	MANE Select
ENST00000267978.10	Ensembl	ENSP00000267978.4	26	MANE Select
NM_001256494.2	RefSeq	NP_001243423.1	26	Standard
NM_001256495.2	RefSeq	NP_001243424.1	26	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Other glycan degradation - Homo sapiens (human)
er associated degradation (erad) pathway
Lysosomal oligosaccharide catabolism
Metabolism of carbohydrates
Metabolism

Biological Process

mannose metabolic process
oligosaccharide catabolic process

Molecular Function

alpha-mannosidase activity
carbohydrate binding
metal ion binding

Cellular Component

nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000565683
Coding exons: 26
Length: 12839
Individuals with no LoFs: 124999
Homozygous LoFs: 1
Heterozygous LoFs: 748
Defined: 125748
p: 0.00298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.155	627	638	0.983	0.0000386	6789
Missense (PolyPhen)		174	201.14	0.86505		2415
Synonymous	0.177	262	266	0.986	0.0000164	2135
Loss of Function	1.06	49	57.7	0.850	0.00000288	601

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.0011	notable
Latino/Admixed American	0.0020	0.0019	notable
Ashkenazi Jewish	0.0010	0.00099	notable
East Asian	0.011	0.011	notable
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.0035	0.0034	notable
South Asian	0.0013	0.0013	notable
Other	0.0027	0.0026	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaves alpha 1,2-, alpha 1,3-, and alpha 1,6-linked mannose residues from glycoproteins. Involved in the degradation of free oligosaccharides in the cytoplasm. {ECO:0000269|PubMed:16848760}.;

Recessive Scores

pRec: 0.267

Intolerance Scores

LoFtool: 0.746
RVIS EVS: -0.1
RVIS percentile EVS: 46.21

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.886

Gene Damage Prediction

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