MAN2A2

protein-coding

mannosidase alpha class 2A member 2, the group of Mannosidases alpha class 2

Gene summary

Predicted to enable alpha-mannosidase activity. Predicted to be involved in N-glycan processing. Predicted to be active in Golgi membrane. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_006122.4

Inheritance

ClinVar variants

P:2U:184B:16

Top phenotype

Neurodevelopmental delay

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr15:90,902,218-90,922,584

External References & Databases

Ensembl (ENSG00000196547)

Transcript & Mutation Effects

hg38 • Region Span ~20.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0024322

Submitter: LiferaOmics

ClinGen MAN2A2- related congenital disorders of glycosylation – Limited- Approval Date: 2025 ClinGen Evidence Breakdown Genetic Evidence = 3.5 points Based on: PMID: 36357165 and PMID: 40628855 Experimental Evidence = 2.5 points Based on: • PMID: 16754854 – Animal model evidence • PMID: 40628855, 8524845 – Expression studies • PMID: 36357165 – Complementation assay and biochemical functional validation ClinGen Total = 6.0 Genetic Evidence – Our Cases Family 1- one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Family 2 - one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 2 total = 1.0 Our Cases Total = 2.0/12 Updated Total Genetic Evidence (ClinGen + Our Cases) ClinGen genetic evidence: 3.5 Our additional cases: +2.0 Updated genetic total = 5.5 Experimental Evidence (unchanged from ClinGen) ClinGen experimental evidence = 2.5 Updated Overall Score Genetic evidence = 5.5 Experimental evidence = 2.5 Updated total = 8.0

disorder of glycosylationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0024322

Submitter: G2P

congenital disorder of glycosylationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015286

Submitter: ClinGen

Pathogenic variants in MAN2A2 were first reported to cause a novel autosomal recessive congenital disorder of glycosylation (CDG) in 2023 [Mahajan et al., PMID:36357165]. MAN2A2 (also known as alpha-MIIx) is a protein coding gene mapped to chromosome 15q16.1. It is predicted to be involved in N-glycan processing, enabling alpha-mannosidase activity. Two recent reports describe three unique variants in humans, including a homozygous truncating variant [PMID:36357165], a missense mutation, and a premature stop codon [PMID:40628855] in association with a MAN2A2-related CDG. Common symptoms among the reported cases include dysmorphic facial features, neurodevelopmental disturbance with mild/moderate intellectual disability, autism spectrum disorder, additional psychiatric issues such as bipolar disorder, social withdrawal, and emotional dysregulation [PMIDS:36357165, 40628855]. This gene-disease relationship is supported by relevant genetic evidence (case-level functional evidence and segregation data [PMIDS:40628855, 8524845]) and experimental evidence (an animal model [PMID:16754854] and expression studies [PMIDS:40628855, 8524845]). A complementation assay for MAN2A2 was recently created, allowing for future screening of variants of uncertain significance (VUS) [PMID:36357165]. Currently, the biological evidence is clear, but clinical evidence is lacking. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on December 1, 2025 (SOP Version 11).

congenital disorder of glycosylationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015286

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAN2A2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 188

not providedTotal: 6

Neurodevelopmental delayTotal: 2

Aganglionic megacolonTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006122.4. 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			1 clinvar	2 clinvar	3 clinvar	6
missense		1 clinvar	179 clinvar	11 clinvar		191
nonsense		1 clinvar				1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	2	184	13	3	202

Highest pathogenic variant AF is 0.0000013681145

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006122.4	RefSeq	NP_006113.2	22	MANE Select
ENST00000559717.6	Ensembl	ENSP00000452948.1	22	MANE Select
NM_001320977.2	RefSeq	NP_001307906.1	23	Standard
ENST00000360468.7	Ensembl	ENSP00000353655.3	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

N-Glycan biosynthesis - Homo sapiens (human)
Vesicle-mediated transport
er associated degradation (erad) pathway
Membrane Trafficking
Post-translational protein modification

Biological Process

mannose metabolic process
protein glycosylation
N-glycan processing
protein deglycosylation

Molecular Function

alpha-mannosidase activity
mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase activity
hydrolase activity, hydrolyzing N-glycosyl compounds
carbohydrate binding
metal ion binding

Cellular Component

Golgi membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360468
Coding exons: 22
Length: 20367
Individuals with no LoFs: 125361
Homozygous LoFs: 0
Heterozygous LoFs: 387
Defined: 125748
p: 0.00154

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.05	650	730	0.891	0.0000471	7476
Missense (PolyPhen)		221	294.27	0.751		3174
Synonymous	-1.45	336	304	1.11	0.0000199	2367
Loss of Function	3.96	27	60.1	0.449	0.00000343	583

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00065	0.00043	rare
Latino/Admixed American	0.0030	0.0030	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.0020	0.0020	notable
South Asian	0.00046	0.00046	rare
Other	0.0029	0.0029	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the first committed step in the biosynthesis of complex N-glycans. It controls conversion of high mannose to complex N-glycans; the final hydrolytic step in the N-glycan maturation pathway.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.285
RVIS EVS: -1.45
RVIS percentile EVS: 3.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.938

Gene Damage Prediction

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