MANF

Summary

MANF (mesencephalic astrocyte derived neurotrophic factor, HGNC:15461) is a protein-coding gene on chromosome 3p21.2, encoding Mesencephalic astrocyte-derived neurotrophic factor (P55145). Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain. It is a selective cancer dependency (DepMap: 31.5% of cell lines).

The protein encoded by this gene is localized in the endoplasmic reticulum (ER) and golgi, and is also secreted. Reducing expression of this gene increases susceptibility to ER stress-induced death and results in cell proliferation. Activity of this protein is important in promoting the survival of dopaminergic neurons. The presence of polymorphisms in the N-terminal arginine-rich region, including a specific mutation that changes an ATG start codon to AGG, have been reported in a variety of solid tumors; however, these polymorphisms were later shown to exist in normal tissues and are thus no longer thought to be tumor-related.

Source: NCBI Gene 7873 — RefSeq curated summary.

At a glance

• Gene–disease (curated): diabetes, deafness, developmental delay, and short stature syndrome (Moderate, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 33 total
• Phenotypes (HPO): 17
• Cancer dependency (DepMap): dependent in 31.5% of screened cell lines
• MANE Select transcript: NM_006010

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15461
Approved symbol	MANF
Name	mesencephalic astrocyte derived neurotrophic factor
Location	3p21.2
Locus type	gene with protein product
Status	Approved
Aliases	ARP
Ensembl gene	ENSG00000145050
Ensembl biotype	protein_coding
OMIM	601916
Entrez	7873

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000446668, ENST00000470900, ENST00000482262, ENST00000528157, ENST00000649711

RefSeq mRNA: 1 — MANE Select: NM_006010 NM_006010

CCDS: CCDS46836

Canonical transcript exons

ENST00000528157 — 4 exons

Exon	Start	End
ENSE00001649110	51388905	51389397
ENSE00001655271	51385291	51385436
ENSE00002502513	51386208	51386335
ENSE00003685078	51387737	51387878

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.2401 / max 404.8858, expressed in 1819 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36764	54.2401	1819

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	98.75	gold quality
type B pancreatic cell	CL:0000169	98.74	gold quality
body of pancreas	UBERON:0001150	98.57	gold quality
right lobe of thyroid gland	UBERON:0001119	98.49	gold quality
left lobe of thyroid gland	UBERON:0001120	98.45	gold quality
mucosa of transverse colon	UBERON:0004991	98.29	gold quality
adenohypophysis	UBERON:0002196	98.28	gold quality
thyroid gland	UBERON:0002046	98.02	gold quality
pancreas	UBERON:0001264	98.01	gold quality
pituitary gland	UBERON:0000007	97.99	gold quality
left testis	UBERON:0004533	97.80	gold quality
right testis	UBERON:0004534	97.68	gold quality
pericardium	UBERON:0002407	97.67	gold quality
rectum	UBERON:0001052	97.47	gold quality
stromal cell of endometrium	CL:0002255	97.39	gold quality
ascending aorta	UBERON:0001496	97.39	gold quality
right lobe of liver	UBERON:0001114	97.38	gold quality
esophagus mucosa	UBERON:0002469	97.37	gold quality
lower esophagus mucosa	UBERON:0035834	97.34	gold quality
thoracic aorta	UBERON:0001515	97.30	gold quality
testis	UBERON:0000473	97.05	gold quality
corpus epididymis	UBERON:0004359	97.03	gold quality
right atrium auricular region	UBERON:0006631	96.94	gold quality
upper lobe of left lung	UBERON:0008952	96.92	gold quality
body of stomach	UBERON:0001161	96.87	gold quality
minor salivary gland	UBERON:0001830	96.82	gold quality
spleen	UBERON:0002106	96.81	gold quality
metanephros cortex	UBERON:0010533	96.76	gold quality
upper lobe of lung	UBERON:0008948	96.72	gold quality
saliva-secreting gland	UBERON:0001044	96.69	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	2238.94
E-CURD-88	yes	113.60
E-HCAD-4	yes	60.92
E-MTAB-9467	yes	54.66
E-CURD-46	yes	50.98
E-HCAD-1	yes	48.96
E-CURD-122	yes	44.33
E-MTAB-8410	yes	43.46
E-ANND-3	yes	22.75
E-HCAD-9	yes	20.54
E-HCAD-11	yes	18.89
E-MTAB-9067	yes	13.13
E-MTAB-10553	yes	12.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, ATF6B, ESR1, TBP, XBP1, YY1

miRNA regulators (miRDB)

18 targeting MANF, 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-144-3P	99.94	73.98	2698
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-203B-3P	97.82	66.27	979
HSA-MIR-634	97.74	67.11	818
HSA-MIR-1226-3P	97.51	66.32	1063
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-6835-5P	95.81	64.27	500
HSA-MIR-764	94.16	64.85	656

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 31.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Armet is a novel secreted mediator of the adaptive pathway of unfolded protein response. (PMID:18561914)
• The widespread expression of MANF together with its evolutionary conserved nature and regulation by brain insults suggest that it has important functions both under normal and pathological conditions in many tissue types. (PMID:18718866)
• structures of MANF and CDNF were solved; structure explains why MANF and CDNF are bifunctional; neurotrophic activity may reside in the N-terminal domain and ER stress response in the C-terminal domain (PMID:19258449)
• Pretreatment with adeno-associated-virus vector containing human MANF reduces the volume of cerebral infarction and facilitates behavioral recovery in experimental stroke rats. (PMID:20685313)
• MANF and C-MANF protect neurons intracellularly as efficiently as Ku70. (PMID:21047780)
• MANF binding to the plasma membrane also required the RTDL sequence and was inhibited with a peptide known to interact with KDELRs, suggesting MANF binds KDELRs at the surface. (PMID:23255601)
• We demonstrate that Armet and Creld2 are genotype-specific ER stress response proteins with substrate specificities, and that aggregation of mutant matrilin-3 is a key disease trigger in MED that could be exploited as a potential therapeutic target (PMID:23956175)
• MANF is a protein that interacts with RTN1-C (PMID:25543119)
• the selective expression of MANF in splenocytes may be involved in plasma cell differentiation and immune regulation. (PMID:26429332)
• the role of two short sequence motifs within the carboxy-(C) terminal domain of MANF in its neuroprotective activity, was studied. (PMID:26720341)
• Our data indicate that increased MANF concentrations in serum are associated with the clinical manifestation of type 1 diabetes in children, but the exact mechanism behind the increase remains elusive (PMID:27356471)
• Serum MANF level was higher in patients with newly diagnosed prediabetes and T2 Diabetes Mellitus than in normal glucose tolerance controls. MANF appears to be associated with Matsuda Index, QUICKI and HOMA-IR in prediabetes patients. (PMID:28216543)
• Single nucleotide polymorphism in MANF gene is associated with systemic lupus erythematosus. (PMID:28740209)
• The results show that GDNF, CDNF, and MANF have divergent effects on dopaminergic neurotransmission, as well as on dopamine synthetizing and metabolizing enzymes. (PMID:29349573)
• Sulfatide binding promotes cellular MANF uptake and cytoprotection from hypoxia-induced cell death. (PMID:29497057)
• High MANF expression is associated with hepatitis B. (PMID:29649564)
• Our results showed MANF alleviated progressive neuronal degeneration and prevented locomotion defects (PMID:29959908)
• MANF has antiapoptotic and mitogenic properties that protect pancreatic beta cells against stress-induced cell death (PMID:30032427)
• the present study demonstrated that the AP-1 complex may be a novel regulator of MANF transcriptional enhancement, and that MANF is a novel downstream target of AP-1, which may indicate a novel role of AP-1 in regulating inflammatory pathways. (PMID:30365109)
• Mesencephalic Astrocyte-Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin-Related Modifier (SUMO)ylation-Related Suppression of NF-kappaB/Snail Signaling Pathway and Epithelial-Mesenchymal Transition. (PMID:31469428)
• Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Upregulated with Therapeutic Fasting in Humans and Diet Fat Withdrawal in Obese Mice. (PMID:31586115)
• Effects of mesencephalic astrocyte-derived neurotrophic factor on cerebral angiogenesis in a rat model of cerebral ischemia. (PMID:31785307)
• Circulating Mesencephalic Astrocyte-Derived Neurotrophic Factor Negatively Correlates With Atrial Apoptosis in Human Chronic Atrial Fibrillation. (PMID:31789884)
• Diagnostic and Prognostic Values of MANF Expression in Hepatocellular Carcinoma. (PMID:32382531)
• Mesencephalic astrocyte-derived neurotrophic factor: A treatment option for parkinson’s disease. (PMID:32472754)
• Hepatocyte-derived MANF alleviates hepatic ischaemia-reperfusion injury via regulating endoplasmic reticulum stress-induced apoptosis in mice. (PMID:33064897)
• The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor. (PMID:33460650)
• The relationship of mesencephalic astrocyte-derived neurotrophic factor with hyperlipidemia in patients with or without type 2 diabetes mellitus. (PMID:33559083)
• Decreased Plasma MANF Levels are Associated with Type 2 Diabetes. (PMID:33766221)
• Correlation of Significantly Decreased Serum Circulating Mesencephalic Astrocyte-Derived Neurotrophic Factor Level With an Increased Risk of Future Cardiovascular Disease in Adult Patients With Growth Hormone Deficiency. (PMID:34220710)
• Analysis of Mesencephalic Astrocyte-derived Neurotrophic Factor in Multiple Myeloma. (PMID:34475050)
• Mesencephalic astrocyte-derived neurotrophic factor reprograms macrophages to ameliorate acetaminophen-induced acute liver injury via p38 MAPK pathway. (PMID:35110525)
• Mesencephalic astrocyte-derived neurotrophic factor attenuates acute lung injury via inhibiting macrophages’ activation. (PMID:35405395)
• MANF Inhibits alpha-Synuclein Accumulation through Activation of Autophagic Pathways. (PMID:35847585)
• Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration. (PMID:36436758)
• A prospective observational study on utility of serum mesencephalic astrocyte-derived neurotrophic factor as a promising prognostic biomarker of severe traumatic brain injury in humans. (PMID:37137461)
• Prognostic potential of serum mesencephalic astrocyte-derived neurotrophic factor in acute intracerebral hemorrhage: a prospective observational study. (PMID:37268902)
• MANF inhibits Sjogren’s syndrome salivary gland epithelial cell apoptosis and antigen expression of Ro52/SSA through endoplasmic reticulum stress/autophagy pathway. (PMID:37393840)
• Deletion of mesencephalic astrocyte-derived neurotrophic factor delays and damages the development of white pulp in spleen. (PMID:38159526)
• MANF Promotes Unexplained Recurrent Miscarriages by Interacting with NPM1 and Downregulating Trophoblast Cell Migration and Invasion. (PMID:38164189)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	manf	ENSDARG00000063177
mus_musculus	Manf	ENSMUSG00000032575
rattus_norvegicus	Manf	ENSRNOG00000014201
drosophila_melanogaster	Manf	FBGN0027095
caenorhabditis_elegans		WBGENE00021888

Paralogs (1): CDNF (ENSG00000185267)

Protein

Protein identifiers

Mesencephalic astrocyte-derived neurotrophic factor — P55145 (reviewed: P55145)

Alternative names: Arginine-rich protein, Protein ARMET

All UniProt accessions (2): P55145, H7C2D6

UniProt curated annotations — full annotation on UniProt →

Function. Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain. Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra. Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons. Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death. Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions. Stabilizes HSPA5/BiP in its substrate-bound ADP state, which facilitates HSPA5/BiP incorporation into chaperone-client complexes during endoplasmic reticulum stress, its interaction with HSPA5/BiP inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange. As a result acts as a repressor of the unfolded protein response (UPR) pathway. Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia. Following secretion by the ER/SR, directly binds to 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells. Sulfatide binding promotes its cellular uptake by endocytosis, and is required for its role in alleviating ER stress and cell toxicity under hypoxic and ER stress conditions. Essential for embryonic lung development. Required for the correct postnatal temporal and structural development of splenic white pulp. Required for the repair-associated myeloid response in skeletal muscle, acts as a regulator of phenotypic transition towards prorepair macrophages in response to muscle injury and as a result limits excessive proinflammatory signaling. Represses RELA expression and therefore NF-kB signaling in the myocardium, as a result limits macrophage infiltration of injured tissue and M1 macrophage differentiation in response to myocardial injury. Required for endochondral ossification in long bones and the skull during postnatal development.

Subunit / interactions. Interacts directly (via SAP domain) with HSPA5/BiP; the interaction inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange. Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4. Interacts (via C-terminus) with ERN1 (via luminal domain); the interaction is decreased in the presence of increasing concentrations of Ca(2+).

Subcellular location. Secreted. Endoplasmic reticulum lumen. Sarcoplasmic reticulum lumen.

Post-translational modifications. May contain sialic acid residues.

Disease relevance. Diabetes, deafness, developmental delay, and short stature syndrome (DDDS) [MIM:620651] An autosomal recessive, multisystem disorder characterized by childhood-onset non-autoimmune diabetes mellitus, short stature, bilateral sensorineural deafness, developmental delay, mildly impaired intellectual development, and microcephaly. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal region may be responsible for neurotrophic activity while the C-terminal region may play a role in the ER stress response. The N-terminal region may be required for lipid sulfatide binding.

Induction. By endoplasmic reticulum stress. By hypoxia. Induced by the ER stressor tunicamycin.

Similarity. Belongs to the ARMET family.

RefSeq proteins (1): NP_006001* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019345	ARMET_C	Domain
IPR036361	SAP_dom_sf	Homologous_superfamily
IPR045332	ARMET_N	Domain
IPR045333	ARMET-like	Family

Pfam: PF10208, PF20145

UniProt features (27 total): helix 9, disulfide bond 4, mutagenesis site 3, turn 3, sequence conflict 2, region of interest 2, signal peptide 1, chain 1, strand 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2W51	X-RAY DIFFRACTION	2.8
2KVD	SOLUTION NMR
2KVE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55145-F1	82.13	0.43

Functional residue map

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

Post-translational modifications (1): 76

Disulfide bonds (4): 30–117, 33–106, 64–75, 151–154

Mutagenesis-validated functional residues (3):

Position	Phenotype
179–182	two-fold increase in secretion.
179	14-fold decrease in secretion.
112	reduced sulfatide binding and uptake by target cells. reduces cytoprotective effect of the wild-type protein. attenuates

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-109582	Hemostasis
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 328 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE45365_NK_CELL_VS_BCELL_UP, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, SWEET_KRAS_ONCOGENIC_SIGNATURE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, CMYB_01, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, AREB6_01

GO Biological Process (6): vasoconstriction of artery involved in ischemic response to lowering of systemic arterial blood pressure (GO:0002014), neuron projection development (GO:0031175), ATF6-mediated unfolded protein response (GO:0036500), dopaminergic neuron differentiation (GO:0071542), regulation of response to endoplasmic reticulum stress (GO:1905897), response to unfolded protein (GO:0006986)

GO Molecular Function (5): RNA binding (GO:0003723), growth factor activity (GO:0008083), sulfatide binding (GO:0120146), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), cytosol (GO:0005829), sarcoplasmic reticulum lumen (GO:0033018), sarcoplasmic reticulum (GO:0016529)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
cytoplasm	2
endoplasmic reticulum	2
regulation of systemic arterial blood pressure by ischemic conditions	1
positive regulation of systemic arterial blood pressure	1
vasoconstriction	1
neuron development	1
plasma membrane bounded cell projection organization	1
ER-nucleus signaling pathway	1
endoplasmic reticulum unfolded protein response	1
neuron differentiation	1
response to endoplasmic reticulum stress	1
regulation of cellular response to stress	1
response to topologically incorrect protein	1
nucleic acid binding	1
receptor ligand activity	1
glycolipid binding	1
endomembrane system	1
intracellular organelle lumen	1
endoplasmic reticulum lumen	1
sarcoplasmic reticulum	1
sarcoplasm	1

Protein interactions and networks

STRING

1150 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MANF	HSPA5	P11021	915
MANF	PSAPL1	Q6NUJ1	718
MANF	NPTN	Q9Y639	688
MANF	XBP1	P17861	673
MANF	RTN1	Q16799	649
MANF	CRELD2	Q6UXH1	644
MANF	ATF6	P18850	638
MANF	PSAP	P07292	636
MANF	PDIA4	P13667	602
MANF	ERN1	O75460	596
MANF	HERPUD1	Q15011	596
MANF	HSP90B1	P14625	590
MANF	NRTN	Q99748	587
MANF	GDNF	P39905	581
MANF	PALLD	Q8WX93	542

IntAct

66 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
STK25	STRN	psi-mi:“MI:0914”(association)	0.900
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
MANF	RTN1	psi-mi:“MI:0915”(physical association)	0.590
MANF	RTN1	psi-mi:“MI:0407”(direct interaction)	0.590
MANF	BCL2L15	psi-mi:“MI:0915”(physical association)	0.590
MATN3	PDIA4	psi-mi:“MI:0914”(association)	0.560
ADAM21	PLXNA2	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
MANF	RTN1	psi-mi:“MI:0915”(physical association)	0.460
RTN1	MANF	psi-mi:“MI:0403”(colocalization)	0.460
BCKDHA	MANF	psi-mi:“MI:0915”(physical association)	0.400
TAOK3	MANF	psi-mi:“MI:0915”(physical association)	0.400
CFAP74	MANF	psi-mi:“MI:0915”(physical association)	0.400
DAB1	MANF	psi-mi:“MI:0915”(physical association)	0.400
MANF	HSPA5	psi-mi:“MI:0915”(physical association)	0.400
NEPRO	MANF	psi-mi:“MI:0915”(physical association)	0.400
SUDS3	MANF	psi-mi:“MI:0915”(physical association)	0.400
FMN2	MANF	psi-mi:“MI:0915”(physical association)	0.400
GTF2H3	MANF	psi-mi:“MI:0915”(physical association)	0.400
ABRAXAS1	MANF	psi-mi:“MI:0915”(physical association)	0.400
FGF10	MANF	psi-mi:“MI:0915”(physical association)	0.400
RAD51AP1	MANF	psi-mi:“MI:0915”(physical association)	0.400
KMT2D	MANF	psi-mi:“MI:0915”(physical association)	0.400
TCP11L1	MANF	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (104): MANF (Two-hybrid), MANF (Affinity Capture-MS), C1orf123 (Co-fractionation), MANF (Co-fractionation), MANF (Affinity Capture-MS), MANF (Affinity Capture-MS), MANF (Proximity Label-MS), MANF (Affinity Capture-MS), BCL2L15 (Affinity Capture-MS), MANF (Affinity Capture-MS), MANF (Affinity Capture-MS), MANF (Affinity Capture-MS), MANF (Proximity Label-MS), TCP11L1 (Proximity Label-MS), MANF (Proximity Label-MS)

ESM2 similar proteins: A8MVJ9, B3M2I7, B3P113, B4GFM7, B4IBX2, B4JT39, B4K5R6, B4LX78, B4NIN8, B4PR07, B4QX46, G5ED46, G5EF60, O44342, O64758, O80977, P0C5H9, P0C5I0, P55145, P80513, P83632, P91928, P93026, P93484, Q09622, Q19267, Q25513, Q295V5, Q2L6K8, Q2L6L1, Q49AH0, Q56ZQ3, Q5M7D4, Q61E63, Q6NUA7, Q7JXF7, Q7Q5L4, Q8CC36, Q8L7E3, Q8T113

Diamond homologs: B3M2I7, B3P113, B4GFM7, B4IBX2, B4JT39, B4K5R6, B4LX78, B4NIN8, B4PR07, B4QX46, P0C5H9, P0C5I0, P55145, P80513, Q295V5, Q49AH0, Q8CC36, Q9CXI5, Q9N3B0, Q9XZ63

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Dengue Virus Attachment and Entry	6	28.8×	2e-05
Epigenetic regulation of gene expression	6	7.9×	7e-03
Viral Infection Pathways	9	5.1×	5e-03
Infectious disease	10	4.6×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
axonogenesis	7	14.8×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

637 predictions. Top by Δscore:

Variant	Effect	Δscore
3:51385351:G:GT	donor_gain	1.0000
3:51386203:TCCAG:T	acceptor_loss	1.0000
3:51386206:A:AG	acceptor_gain	1.0000
3:51386206:AGTT:A	acceptor_loss	1.0000
3:51386207:G:A	acceptor_loss	1.0000
3:51386207:G:GA	acceptor_gain	1.0000
3:51386207:GTT:G	acceptor_gain	1.0000
3:51386207:GTTT:G	acceptor_gain	1.0000
3:51386332:GTTG:G	donor_gain	1.0000
3:51386333:TTG:T	donor_gain	1.0000
3:51386335:GGTA:G	donor_loss	1.0000
3:51386336:G:GG	donor_gain	1.0000
3:51386337:TAA:T	donor_loss	1.0000
3:51386338:AAGTA:A	donor_loss	1.0000
3:51387729:T:TA	acceptor_gain	1.0000
3:51387735:A:AG	acceptor_gain	1.0000
3:51387735:AGT:A	acceptor_gain	1.0000
3:51387736:G:GA	acceptor_gain	1.0000
3:51387736:GT:G	acceptor_gain	1.0000
3:51387736:GTG:G	acceptor_gain	1.0000
3:51387736:GTGC:G	acceptor_gain	1.0000
3:51387736:GTGCT:G	acceptor_gain	1.0000
3:51387860:A:G	donor_gain	1.0000
3:51387874:GTATG:G	donor_gain	1.0000
3:51387875:TATG:T	donor_gain	1.0000
3:51387880:T:G	donor_loss	1.0000
3:51388903:A:AG	acceptor_gain	1.0000
3:51388904:G:GA	acceptor_gain	1.0000
3:51388904:GA:G	acceptor_gain	1.0000
3:51388904:GAC:G	acceptor_gain	1.0000

AlphaMissense

1187 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:51387737:T:C	C75R	0.999
3:51387749:G:T	G79W	0.999
3:51387750:G:A	G79E	0.999
3:51387768:C:A	A85D	0.999
3:51387830:T:C	C106R	0.999
3:51387831:G:A	C106Y	0.999
3:51387840:T:C	L109P	0.999
3:51387861:T:A	I116K	0.999
3:51387864:G:A	C117Y	0.999
3:51388959:T:C	L140P	0.999
3:51389009:A:G	K157E	0.999
3:51389011:G:C	K157N	0.999
3:51389011:G:T	K157N	0.999
3:51386304:G:A	C64Y	0.998
3:51387737:T:A	C75S	0.998
3:51387738:G:C	C75S	0.998
3:51387749:G:A	G79R	0.998
3:51387749:G:C	G79R	0.998
3:51387750:G:T	G79V	0.998
3:51387753:C:A	A80D	0.998
3:51387764:G:C	A84P	0.998
3:51387830:T:A	C106S	0.998
3:51387831:G:C	C106S	0.998
3:51387831:G:T	C106F	0.998
3:51387832:T:G	C106W	0.998
3:51387851:G:C	D113H	0.998
3:51387861:T:G	I116R	0.998
3:51387863:T:A	C117S	0.998
3:51387863:T:C	C117R	0.998
3:51387864:G:C	C117S	0.998

dbSNP variants (sampled 300 via entrez): RS1001527198 (3:51385791 G>A,T), RS1001581439 (3:51386006 G>C), RS1003256690 (3:51387629 A>C), RS1003615233 (3:51387293 A>G,T), RS1004328391 (3:51383985 G>T), RS1004379314 (3:51384508 A>G), RS1005340086 (3:51389284 C>A,T), RS1005998005 (3:51385437 G>A,T), RS1006671664 (3:51388517 T>A,C), RS1007671440 (3:51386811 A>T), RS1007957525 (3:51389599 C>G,T), RS1008214255 (3:51383420 G>A,C), RS1010174387 (3:51384953 C>G,T), RS1010303110 (3:51385192 G>A), RS1010565965 (3:51388069 C>T)

Disease associations

OMIM: gene MIM:601916 | disease phenotypes: MIM:117650

GenCC curated gene-disease

Disease	Classification	Inheritance
diabetes, deafness, developmental delay, and short stature syndrome	Moderate	Autosomal recessive

Mondo (2): cerebrocostomandibular syndrome (MONDO:0007301), diabetes, deafness, developmental delay, and short stature syndrome (MONDO:0957997)

Orphanet (1): Cerebrocostomandibular syndrome (Orphanet:1393)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000815	Hypergonadotropic hypogonadism
HP:0001263	Global developmental delay
HP:0001596	Alopecia
HP:0002650	Scoliosis
HP:0003621	Juvenile onset
HP:0004322	Short stature
HP:0005978	Type II diabetes mellitus
HP:0011003	High myopia
HP:0011462	Young adult onset
HP:0030341	Decreased circulating follicle stimulating hormone concentration
HP:0030344	Decreased circulating luteinizing hormone level
HP:0031098	Decreased thyroid-stimulating hormone level
HP:0034323	Reduced circulating growth hormone concentration
HP:0040075	Hypopituitarism

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006479_74	Diverticular disease	8.000000e-07
GCST008843_1	Depressive symptom (appetite changes) (binary trait)	9.000000e-09
GCST008848_2	Depressive symptoms (sum-score)	1.000000e-09
GCST008849_3	Depressive symptoms (binary sum-score)	1.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease
EFO:0007006	depressive symptom measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562538	Cerebrocostomandibular Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, affects cotreatment	6
sodium arsenite	affects cotreatment, increases abundance, increases expression, affects expression, decreases expression	5
Cyclosporine	increases expression	5
Tunicamycin	increases expression	4
Cisplatin	decreases expression, decreases reaction, increases expression	3
Arsenic	decreases expression, decreases methylation, increases abundance, affects cotreatment	2
Estradiol	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
Thapsigargin	increases expression	2
Okadaic Acid	increases expression	2
lead acetate	increases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
sulindac sulfide	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
dinophysistoxin 1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
chloropicrin	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
fenpyroximate	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
ICG 001	decreases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
bisphenol S	affects expression	1
jinfukang	increases expression	1

Clinical trials (associated diseases)

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