EMC1

Summary

EMC1 (ER membrane protein complex subunit 1, HGNC:28957) is a protein-coding gene on chromosome 1p36.13, encoding ER membrane protein complex subunit 1 (Q8N766). Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins. It is a selective cancer dependency (DepMap: 50.9% of cell lines).

This gene encodes a single-pass type I transmembrane protein, which is a subunit of the endoplasmic reticulum membrane protein complex (EMC). Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23065 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar atrophy, visual impairment, and psychomotor retardation; (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,372 total — 53 pathogenic, 38 likely-pathogenic
• Phenotypes (HPO): 46
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 50.9% of screened cell lines
• MANE Select transcript: NM_015047

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28957
Approved symbol	EMC1
Name	ER membrane protein complex subunit 1
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000127463
Ensembl biotype	protein_coding
OMIM	616846
Entrez	23065

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 31 protein_coding, 10 retained_intron, 10 nonsense_mediated_decay

ENST00000375199, ENST00000375208, ENST00000461353, ENST00000462505, ENST00000467423, ENST00000475079, ENST00000477853, ENST00000480380, ENST00000486238, ENST00000486405, ENST00000488681, ENST00000494770, ENST00000685099, ENST00000685594, ENST00000688219, ENST00000688332, ENST00000688538, ENST00000688667, ENST00000688918, ENST00000689748, ENST00000690451, ENST00000690732, ENST00000690823, ENST00000691945, ENST00000692207, ENST00000692400, ENST00000693007, ENST00000911101, ENST00000911102, ENST00000911103, ENST00000911104, ENST00000911105, ENST00000911106, ENST00000911107, ENST00000911108, ENST00000911109, ENST00000933101, ENST00000933102, ENST00000933103, ENST00000933104, ENST00000933105, ENST00000933106, ENST00000933107, ENST00000933108, ENST00000933109, ENST00000960178, ENST00000960179, ENST00000960180, ENST00000960181, ENST00000960182, ENST00000960183

RefSeq mRNA: 6 — MANE Select: NM_015047 NM_001271427, NM_001271428, NM_001271429, NM_001375820, NM_001375821, NM_015047

CCDS: CCDS190, CCDS59190, CCDS59191, CCDS90871

Canonical transcript exons

ENST00000477853 — 23 exons

Exon	Start	End
ENSE00000872911	19235130	19235252
ENSE00000908596	19238795	19238857
ENSE00000908598	19238017	19238139
ENSE00000908600	19237142	19237238
ENSE00000908602	19232936	19233135
ENSE00000908604	19232624	19232773
ENSE00000908606	19231261	19231422
ENSE00000908608	19230844	19230963
ENSE00001265682	19251415	19251524
ENSE00001638237	19242345	19242473
ENSE00001638308	19240297	19240446
ENSE00001664299	19241016	19241142
ENSE00001676545	19243614	19243707
ENSE00001740696	19239818	19239985
ENSE00001797601	19244906	19245030
ENSE00001801402	19239231	19239302
ENSE00001943800	19215660	19219482
ENSE00003461478	19222624	19222834
ENSE00003498692	19223396	19223569
ENSE00003538409	19220764	19220848
ENSE00003597230	19243950	19244015
ENSE00003641737	19227313	19227450
ENSE00003672321	19219569	19219698

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 95.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.9160 / max 288.6936, expressed in 1818 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10650	40.9160	1818

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	95.31	gold quality
islet of Langerhans	UBERON:0000006	93.17	gold quality
sural nerve	UBERON:0015488	90.28	gold quality
ventricular zone	UBERON:0003053	90.02	gold quality
colonic epithelium	UBERON:0000397	89.76	gold quality
gastrocnemius	UBERON:0001388	89.42	gold quality
cartilage tissue	UBERON:0002418	89.22	gold quality
adrenal tissue	UBERON:0018303	89.16	gold quality
muscle of leg	UBERON:0001383	89.06	gold quality
cortical plate	UBERON:0005343	89.03	gold quality
cervix squamous epithelium	UBERON:0006922	88.39	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.31	gold quality
smooth muscle tissue	UBERON:0001135	88.11	gold quality
right ovary	UBERON:0002118	88.01	gold quality
left ovary	UBERON:0002119	87.81	gold quality
ganglionic eminence	UBERON:0004023	87.59	gold quality
body of uterus	UBERON:0009853	87.56	gold quality
thoracic aorta	UBERON:0001515	87.43	gold quality
ascending aorta	UBERON:0001496	87.41	gold quality
descending thoracic aorta	UBERON:0002345	87.41	gold quality
left coronary artery	UBERON:0001626	87.37	gold quality
cerebellar cortex	UBERON:0002129	87.33	gold quality
cerebellar hemisphere	UBERON:0002245	87.33	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.32	gold quality
right coronary artery	UBERON:0001625	87.18	gold quality
prefrontal cortex	UBERON:0000451	87.08	gold quality
pancreas	UBERON:0001264	87.06	gold quality
ovary	UBERON:0000992	87.05	gold quality
ectocervix	UBERON:0012249	87.00	gold quality
mucosa of transverse colon	UBERON:0004991	86.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

143 targeting EMC1, 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-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7153-5P	99.94	68.89	1006

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 50.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 3)

• EMC1 is a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum. (PMID:26942288)
• The authors find that a member of the endoplasmic reticulum membrane protein complex (EMC) called EMC1 promotes SV40 virus endoplasmic reticulum membrane transport and infection. (PMID:28012275)
• Novel truncating and missense variants extending the spectrum of EMC1-related phenotypes, causing autism spectrum disorder, severe global development delay and visual impairment. (PMID:32092440)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	emc1	ENSDARG00000057255
mus_musculus	Emc1	ENSMUSG00000078517
rattus_norvegicus	Emc1	ENSRNOG00000018097
drosophila_melanogaster	EMC1	FBGN0037530
caenorhabditis_elegans		WBGENE00019209

Protein

Protein identifiers

ER membrane protein complex subunit 1 — Q8N766 (reviewed: Q8N766)

All UniProt accessions (13): Q8N766, A0A8I5KQA0, A0A8I5KRL9, A0A8I5KSM5, A0A8I5KTE8, A0A8I5KW55, A0A8I5KWE3, A0A8I5KWP6, A0A8I5KXE1, A0A8I5QKP5, H7C4E3, H7C5A2, Q5TG59

UniProt curated annotations — full annotation on UniProt →

Function. Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins. Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues. Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices. It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes. By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors. By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes.

Subunit / interactions. Component of the ER membrane protein complex (EMC).

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR) [MIM:616875] An autosomal recessive, neurodegenerative disorder characterized by developmental delay, intellectual disability, hypotonia, scoliosis, cerebellar atrophy, and variable dysmorphic features. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the EMC1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N766-1	1	yes
Q8N766-2	2
Q8N766-3	3
Q8N766-4	4

RefSeq proteins (6): NP_001258356, NP_001258357, NP_001258358, NP_001362749, NP_001362750, NP_055862* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011047	Quinoprotein_ADH-like_sf	Homologous_superfamily
IPR011678	EMC1_C	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR026895	EMC1	Family
IPR058545	Beta-prop_EMC1_1st	Domain

Pfam: PF07774, PF25293

UniProt features (132 total): strand 87, turn 11, helix 7, sequence variant 7, sequence conflict 7, splice variant 3, glycosylation site 3, topological domain 2, disulfide bond 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8J0O	ELECTRON MICROSCOPY	3.32
7ADO	ELECTRON MICROSCOPY	3.39
6WW7	ELECTRON MICROSCOPY	3.4
8EOI	ELECTRON MICROSCOPY	3.4
8J0N	ELECTRON MICROSCOPY	3.47
7ADP	ELECTRON MICROSCOPY	3.6
8S9S	ELECTRON MICROSCOPY	3.6
9ZZ6	ELECTRON MICROSCOPY	4.16
6Z3W	ELECTRON MICROSCOPY	6.4
9C7V	ELECTRON MICROSCOPY	6.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N766-F1	87.67	0.68

Functional residue map

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

Disulfide bonds (2): 227–237, 338–368

Glycosylation sites (3): 370, 818, 913

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 231 (showing top): MODULE_206, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, COATES_MACROPHAGE_M1_VS_M2_UP, LIAO_METASTASIS, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, HIF1_Q3, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, MULLIGHAN_NPM1_SIGNATURE_3_DN, GOBP_MEMBRANE_ORGANIZATION, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, MILI_PSEUDOPODIA_CHEMOTAXIS_DN

GO Biological Process (2): protein insertion into ER membrane by stop-transfer membrane-anchor sequence (GO:0045050), tail-anchored membrane protein insertion into ER membrane (GO:0071816)

GO Molecular Function (2): protein binding (GO:0005515), membrane insertase activity (GO:0032977)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), protein-containing complex (GO:0032991), EMC complex (GO:0072546), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein insertion into ER membrane	2
binding	1
establishment of protein localization to membrane	1
protein carrier activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
cellular_component	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EMC1	EMC6	Q9BV81	961
EMC1	EMC4	Q5J8M3	946
EMC1	EMC2	Q15006	926
EMC1	MMGT1	Q8N4V1	914
EMC1	EMC3	Q9P0I2	892
EMC1	EMC7	Q9NPA0	864
EMC1	EMC8	O43402	774
EMC1	EMC9	Q9Y3B6	736
EMC1	EMC10	Q5UCC4	723
EMC1	UBAC2	Q8NBM4	675
EMC1	TOMM5	Q8N4H5	629
EMC1	CANX	P27824	597
EMC1	DNAJB14	Q8TBM8	587
EMC1	DDOST	P39656	580
EMC1	SGTA	O43765	572
EMC1	DNAJC18	Q9H819	572

IntAct

177 interactions, top by confidence:

A	B	Type	Score
EMC2	EMC8	psi-mi:“MI:0914”(association)	0.940
EMC8	EMC2	psi-mi:“MI:0914”(association)	0.940
EMC2	EMC10	psi-mi:“MI:0914”(association)	0.800
EMC7	EMC8	psi-mi:“MI:0914”(association)	0.790
EMC3	EMC8	psi-mi:“MI:0914”(association)	0.730
MMGT1	EMC8	psi-mi:“MI:0914”(association)	0.730
TMED9	TMED10	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EMC1		psi-mi:“MI:0915”(physical association)	0.660
EMC1	EMC8	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640

BioGRID (586): EMC1 (Affinity Capture-MS), EMC1 (Affinity Capture-MS), EMC1 (Affinity Capture-MS), EMC1 (Affinity Capture-MS), EMC1 (Affinity Capture-MS), ENO1 (Affinity Capture-MS), EMC8 (Affinity Capture-MS), EMC2 (Affinity Capture-MS), CANX (Affinity Capture-MS), EMC3 (Affinity Capture-MS), MMGT1 (Affinity Capture-MS), EMC7 (Affinity Capture-MS), EMC1 (Affinity Capture-MS), EMC1 (Affinity Capture-MS), EMC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3NGV2, A2VE47, A4IG72, A7E2V1, D3Z2R5, F1PCT7, O43909, P02786, P04844, P25235, P57716, Q07891, Q0VCN6, Q28120, Q28DV7, Q2V905, Q5R9Q9, Q5RBM1, Q5RDH6, Q5XIA1, Q5ZJH2, Q5ZL00, Q62351, Q64255, Q6DDX8, Q6NZ07, Q7TMC8, Q8BXQ2, Q8C7X2, Q8CGU6, Q8K224, Q8N766, Q8N961, Q8R553, Q8VCM8, Q8VDL4, Q92542, Q969N2, Q969V3, Q99JH7

Diamond homologs: O13981, Q5R7K6, Q5ZL00, Q6NRB9, Q8C7X2, Q8N766

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EMC1	“form complex”	“Endoplasmic reticulum membrane complex- EMC9 variant”	binding
EMC1	“form complex”	“Endoplasmic reticulum membrane complex, EMC8 variant”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 183 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
SLC-mediated transmembrane transport	11	5.2×	2e-03
Transport of small molecules	17	3.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
tail-anchored membrane protein insertion into ER membrane	9	52.7×	1e-11
sodium ion import across plasma membrane	5	19.5×	1e-03
ERAD pathway	9	10.2×	1e-04
endoplasmic reticulum to Golgi vesicle-mediated transport	8	6.8×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1372 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	53
Likely pathogenic	38
Uncertain significance	732
Likely benign	453
Benign	29

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1019587	NM_015047.3(EMC1):c.1429del (p.Ala477fs)	Pathogenic
1023665	NM_015047.3(EMC1):c.2113C>T (p.Gln705Ter)	Pathogenic
1052500	NM_015047.3(EMC1):c.1790del (p.Gly597fs)	Pathogenic
1357922	NM_015047.3(EMC1):c.205C>T (p.Arg69Ter)	Pathogenic
1385137	NM_015047.3(EMC1):c.2503C>T (p.Gln835Ter)	Pathogenic
1418611	NM_015047.3(EMC1):c.2564dup (p.Ile856fs)	Pathogenic
1429859	NM_015047.3(EMC1):c.812_813insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCGAGACCATCCCGGCTAAAACGGTGAAACCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAATTTGGAAGTGG (p.Gly271_Phe272insAlaGlyArgGlyGlySerArgLeuTer)	Pathogenic
1444028	NM_015047.3(EMC1):c.1096_1097del (p.Leu366fs)	Pathogenic
1451366	NM_015047.3(EMC1):c.1013del (p.Cys338fs)	Pathogenic
1452472	NM_015047.3(EMC1):c.2239_2240del (p.Ser747fs)	Pathogenic
1452487	NM_015047.3(EMC1):c.877del (p.Leu293fs)	Pathogenic
1453036	NM_015047.3(EMC1):c.1164del (p.Asp388fs)	Pathogenic
1453913	NC_000001.10:g.(?19563616)(19571544_?)del	Pathogenic
1455289	NM_015047.3(EMC1):c.808dup (p.Ser270fs)	Pathogenic
1455932	NM_015047.3(EMC1):c.330G>A (p.Trp110Ter)	Pathogenic
1456458	NC_000001.10:g.(?19549098)(19553964_?)del	Pathogenic
1457221	NM_015047.3(EMC1):c.1676del (p.Gln559fs)	Pathogenic
1458063	NC_000001.10:g.(?19545797)(19578003_?)del	Pathogenic
1459220	NC_000001.10:g.(?19559098)(19561766_?)del	Pathogenic
1460429	NM_015047.3(EMC1):c.412_419dup (p.Arg141fs)	Pathogenic
1470767	NM_015047.3(EMC1):c.1A>G (p.Met1Val)	Pathogenic
1805606	NM_015047.3(EMC1):c.661C>T (p.Gln221Ter)	Pathogenic
1897028	NM_015047.3(EMC1):c.579del (p.Phe194fs)	Pathogenic
1909892	NM_015047.3(EMC1):c.1219_1220del (p.Ile407fs)	Pathogenic
1957802	NM_015047.3(EMC1):c.542dup (p.Tyr181Ter)	Pathogenic
2014464	NM_015047.3(EMC1):c.2026_2050dup (p.Tyr684fs)	Pathogenic
2050646	NM_015047.3(EMC1):c.2686dup (p.Ile896fs)	Pathogenic
2093370	NM_015047.3(EMC1):c.1674dup (p.Gln559fs)	Pathogenic
2097027	NM_015047.3(EMC1):c.1486C>T (p.Gln496Ter)	Pathogenic
2105466	NM_015047.3(EMC1):c.488G>A (p.Trp163Ter)	Pathogenic

SpliceAI

3942 predictions. Top by Δscore:

Variant	Effect	Δscore
1:19219267:C:A	donor_gain	1.0000
1:19219479:CAAC:C	acceptor_gain	1.0000
1:19219481:ACC:A	acceptor_loss	1.0000
1:19219482:CCTGG:C	acceptor_loss	1.0000
1:19219483:CTGG:C	acceptor_loss	1.0000
1:19219484:T:C	acceptor_loss	1.0000
1:19222618:A:AC	donor_gain	1.0000
1:19222619:C:CC	donor_gain	1.0000
1:19222619:CTCA:C	donor_gain	1.0000
1:19222620:TCA:T	donor_loss	1.0000
1:19222622:A:AC	donor_gain	1.0000
1:19222622:ACT:A	donor_gain	1.0000
1:19222623:C:CA	donor_gain	1.0000
1:19222623:CT:C	donor_gain	1.0000
1:19222623:CTC:C	donor_gain	1.0000
1:19222623:CTCA:C	donor_gain	1.0000
1:19222623:CTCAG:C	donor_gain	1.0000
1:19222627:G:C	donor_gain	1.0000
1:19222830:TGGTA:T	acceptor_gain	1.0000
1:19222833:TA:T	acceptor_gain	1.0000
1:19222835:C:CC	acceptor_gain	1.0000
1:19223471:C:CA	donor_gain	1.0000
1:19223565:AGGCT:A	acceptor_gain	1.0000
1:19223566:GGCT:G	acceptor_gain	1.0000
1:19223568:CT:C	acceptor_gain	1.0000
1:19223569:TC:T	acceptor_loss	1.0000
1:19223570:C:CA	acceptor_loss	1.0000
1:19223570:C:CC	acceptor_gain	1.0000
1:19223571:T:A	acceptor_loss	1.0000
1:19227449:TC:T	acceptor_gain	1.0000

AlphaMissense

6447 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:19219309:C:A	W992C	1.000
1:19219309:C:G	W992C	1.000
1:19219311:A:G	W992R	1.000
1:19219311:A:T	W992R	1.000
1:19219314:C:G	A991P	1.000
1:19219338:C:G	A983P	1.000
1:19219370:A:G	L972P	1.000
1:19219382:A:T	V968D	1.000
1:19219387:G:C	S966R	1.000
1:19219387:G:T	S966R	1.000
1:19219389:T:G	S966R	1.000
1:19219391:A:T	I965N	1.000
1:19219418:A:G	L956P	1.000
1:19219418:A:T	L956Q	1.000
1:19219423:G:C	D954E	1.000
1:19219423:G:T	D954E	1.000
1:19219424:T:A	D954V	1.000
1:19219424:T:C	D954G	1.000
1:19219424:T:G	D954A	1.000
1:19219425:C:G	D954H	1.000
1:19219426:A:C	F953L	1.000
1:19219426:A:T	F953L	1.000
1:19219427:A:C	F953C	1.000
1:19219427:A:G	F953S	1.000
1:19219428:A:G	F953L	1.000
1:19219428:A:T	F953I	1.000
1:19219579:G:A	S931F	1.000
1:19219580:A:G	S931P	1.000
1:19219585:A:G	L929P	1.000
1:19227329:C:G	R729P	1.000

dbSNP variants (sampled 300 via entrez): RS1000123402 (1:19234762 C>G), RS1000261098 (1:19252229 T>A), RS1000311749 (1:19253195 T>A), RS1000316011 (1:19247752 C>T), RS1000371126 (1:19241441 A>C), RS1000417871 (1:19246372 A>G,T), RS1000418775 (1:19247357 C>T), RS1000592160 (1:19252379 C>T), RS1000638827 (1:19246281 T>G), RS1000751135 (1:19247720 C>T), RS1000794471 (1:19235198 A>G), RS1000938591 (1:19228336 T>G), RS1000950226 (1:19241608 G>A), RS1001047817 (1:19252026 AAAAC>A), RS1001135476 (1:19241429 C>G,T)

Disease associations

OMIM: gene MIM:616846 | disease phenotypes: MIM:616875, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar atrophy, visual impairment, and psychomotor retardation;	Strong	Autosomal recessive
complex neurodevelopmental disorder with motor features	Strong	Autosomal dominant
global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder with motor features	Moderate	AR
complex neurodevelopmental disorder with motor features	Moderate	AD

Mondo (7): cerebellar atrophy, visual impairment, and psychomotor retardation; (MONDO:0014811), inherited retinal dystrophy (MONDO:0019118), congenital anomaly of kidney and urinary tract (MONDO:0019719), obesity disorder (MONDO:0011122), microcephaly (MONDO:0001149), global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome (MONDO:0018822), complex neurodevelopmental disorder with motor features (MONDO:0100516)

Orphanet (4): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Renal or urinary tract malformation (Orphanet:93545), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000188	Short upper lip
HP:0000212	Gingival overgrowth
HP:0000253	Progressive microcephaly
HP:0000278	Retrognathia
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000377	Abnormal pinna morphology
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000512	Abnormal electroretinogram
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000750	Delayed speech and language development
HP:0001045	Vitiligo
HP:0001212	Prominent fingertip pads
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001999	Abnormal facial shape

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000597_10	Brain structure	1.000000e-07
GCST007001_1	Cerebrospinal AB1-42 levels in normal cognition	5.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004670	beta-amyloid 1-42 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D058499	Retinal Dystrophies	C11.768.585.658
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067163 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.54	Kd	288.4	nM	CHEMBL3752910
6.53	ED50	295.2	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149858: Binding affinity to human EMC1 incubated for 45 mins by Kinobead based pull down assay	kd	0.2883	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, increases reaction, decreases expression, increases abundance	4
bisphenol S	increases expression, affects cotreatment, decreases expression	2
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Fluorouracil	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methotrexate	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652900	Binding	Binding affinity to human EMC1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	PHASE4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	PHASE4	TERMINATED	Supplements for Controlling Resistance to Insulin
NCT00729963	PHASE4	COMPLETED	Sibutramine Versus Continuous Positive Airway Pressure (CPAP)in Obstructive Sleep Apnea (OSA) Patients