SEC61A1

Summary

SEC61A1 (SEC61 translocon subunit alpha 1, HGNC:18276) is a protein-coding gene on chromosome 3q21.3, encoding Protein transport protein Sec61 subunit alpha isoform 1 (P61619). Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER). It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

The protein encoded by this gene belongs to the SECY/SEC61- alpha family. It appears to play a crucial role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. This protein found to be tightly associated with membrane-bound ribosomes, either directly or through adaptor proteins. This gene encodes an alpha subunit of the heteromeric SEC61 complex, which also contains beta and gamma subunits.

Source: NCBI Gene 29927 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperuricemic nephropathy, familial juvenile type 4 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 202 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_013336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18276
Approved symbol	SEC61A1
Name	SEC61 translocon subunit alpha 1
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000058262
Ensembl biotype	protein_coding
OMIM	609213
Entrez	29927

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 10 protein_coding, 8 retained_intron, 6 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000243253, ENST00000424880, ENST00000464451, ENST00000481210, ENST00000483956, ENST00000491668, ENST00000498837, ENST00000699266, ENST00000699267, ENST00000699268, ENST00000699269, ENST00000699270, ENST00000699271, ENST00000699272, ENST00000699273, ENST00000699274, ENST00000699275, ENST00000699280, ENST00000699281, ENST00000699282, ENST00000699283, ENST00000699284, ENST00000881448, ENST00000881449, ENST00000937479

RefSeq mRNA: 3 — MANE Select: NM_013336 NM_001400328, NM_001400329, NM_013336

CCDS: CCDS3046, CCDS93366, CCDS93367

Canonical transcript exons

ENST00000243253 — 12 exons

Exon	Start	End
ENSE00000777651	128064877	128065037
ENSE00000777652	128060508	128060661
ENSE00000777655	128056709	128056840
ENSE00000777658	128052835	128052902
ENSE00001079473	128069476	128071683
ENSE00001374740	128052437	128052559
ENSE00003551486	128067983	128068059
ENSE00003578036	128067421	128067612
ENSE00003579887	128066954	128067151
ENSE00003628952	128055516	128055581
ENSE00003630270	128055673	128055751
ENSE00003790598	128060102	128060211

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 274.2858 / max 1703.9442, expressed in 1828 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38419	269.9258	1828
38423	2.5011	1209
38418	0.7134	319
38422	0.6576	416
38424	0.4879	279

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.24	gold quality
stromal cell of endometrium	CL:0002255	99.23	gold quality
islet of Langerhans	UBERON:0000006	98.48	gold quality
adenohypophysis	UBERON:0002196	98.43	gold quality
right lobe of liver	UBERON:0001114	98.07	gold quality
smooth muscle tissue	UBERON:0001135	98.02	gold quality
body of stomach	UBERON:0001161	97.96	gold quality
pituitary gland	UBERON:0000007	97.87	gold quality
left adrenal gland	UBERON:0001234	97.87	gold quality
upper lobe of left lung	UBERON:0008952	97.86	gold quality
left adrenal gland cortex	UBERON:0035825	97.86	gold quality
gall bladder	UBERON:0002110	97.79	gold quality
pancreas	UBERON:0001264	97.73	gold quality
endocervix	UBERON:0000458	97.69	gold quality
right adrenal gland	UBERON:0001233	97.68	gold quality
minor salivary gland	UBERON:0001830	97.66	gold quality
saliva-secreting gland	UBERON:0001044	97.62	gold quality
upper lobe of lung	UBERON:0008948	97.61	gold quality
right adrenal gland cortex	UBERON:0035827	97.58	gold quality
adrenal gland	UBERON:0002369	97.56	gold quality
left uterine tube	UBERON:0001303	97.54	gold quality
right lobe of thyroid gland	UBERON:0001119	97.46	gold quality
stomach	UBERON:0000945	97.43	gold quality
adrenal cortex	UBERON:0001235	97.42	gold quality
ascending aorta	UBERON:0001496	97.42	gold quality
thoracic aorta	UBERON:0001515	97.40	gold quality
ectocervix	UBERON:0012249	97.36	gold quality
right coronary artery	UBERON:0001625	97.35	gold quality
rectum	UBERON:0001052	97.33	gold quality
metanephros cortex	UBERON:0010533	97.32	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	46.89
E-CURD-122	yes	43.83
E-HCAD-1	yes	10.46
E-MTAB-6524	no	84.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting SEC61A1, 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-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548P	99.98	72.25	3784
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-590-3P	99.96	74.34	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-4743-3P	99.62	68.12	2095

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 30)

• analysis of translocation through the Sec61 translocon by the nascent polypeptide structure within the ribosome (PMID:18480044)
• At the cellular level, two different calmodulin antagonists stimulated calcium release from the endoplasmic reticulum through SEC61 channels. (PMID:21102557)
• Silencing the SEC61A1 gene using two different siRNAs in HeLa cells for 96 hours had little effect on cell growth and viability. However, calcium leakage from the ER was greatly decreased in the SEC61A1-silenced cells. (PMID:21406962)
• The present study indicates that Sec61alpha is a host protein involved in Ebola virus (EBOV) replication, specifically in EBOV genome transcription and replication. (PMID:21987770)
• The human SEC61A1 gene is essential for cell growth and viability. (PMID:22375059)
• Short secretory proteins appear to be ubiquitously transported across the ER membrane through the Sec61 translocon. (PMID:22505607)
• BiP limits ER Ca(2+) leakage through the Sec61 complex by binding to the ER lumenal loop 7 of Sec61alpha in the vicinity of tyrosine 344. (PMID:22796945)
• Cotransin, a substrate-selective Sec61 inhibitor, traps nascent transmembrane domains in the cytosolic vestibule, permitting detailed interrogation of an early pre-integration intermediate. (PMID:24497544)
• Unpicking the central dogma of molecular biology step-by-step identifies the Sec61 translocon as the target of anti-inflammatory activity of mycolactone, explaining why production of Sec61-dependent proteins (secretory, ER resident and membrane bound) is lost even though transcription and translation are unaffected. (PMID:24699819)
• Sec61 complex is calcium permeable, the Sec61 complex is tightly regulated in its equilibrium between the closed and open conformations, or “gated”, by ligands, such as signal peptides of the transport substrates (PMID:24934166)
• BiP facilitates Sec61 channel closure (i.e. limits ER Ca(2+) leakage) via the Sec61 channel with the help of ERj3 and ERj6 (PMID:26085089)
• Nuclear envelope associated endosome-mediated transfer depends on the nuclear envelope proteins SUN1 and SUN2, as well as the Sec61 translocon complex. (PMID:26356418)
• EPO (7q22) and SEC-61(7p11) emerged as new candidate genes susceptible to genetic losses with 57.7% deletions identified in regions on chromosome 7. (PMID:27282568)
• Tomography densities at subnanometer resolution revealed an intricate network of interactions between the ribosome, Sec61 and accessory translocon components that assist in protein transport, membrane insertion and maturation (PMID:27373685)
• findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease; we highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for autosomal-dominant tubulo-interstitial kidney disease (PMID:27392076)
• data provide definitive genetic evidence that Sec61 is the host receptor mediating the diverse immunomodulatory effects of mycolactone and identify Sec61 as a novel regulator of immune cell functions. (PMID:27821549)
• The discovery of export-specific sec61 mutants and of mammalian ER-associated degradation (ERAD) substrates whose export is dependent on the 19S regulatory particle suggest that dismissal of a role of Sec61 in export may have been premature. (PMID:27932072)
• the effect of mycolactone on transmembrane protein biogenesis depends on how the nascent chain initially engages the Sec61 complex. (PMID:28219954)
• The authors propose that the Sec61-IRE1alpha complex defines the extent of IRE1alpha activity and may determine cell fate decisions during endoplasmic reticulum stress conditions. (PMID:28504640)
• The direct contribution of Sec61 to antigen cross-presentation, endosome-to-cytosol export, and endoplasmic reticulum-to-cytosol export. (PMID:28679634)
• SEC61A1-V85D triggered the terminal unfolded protein response in multiple myeloma cell lines. (PMID:28782633)
• Shows that inhibition of Sec61 by mycolactone drives rapid and broad translational reprogramming of a subset of genes involved in stress responses that is initially protective but ultimately leads to cell death (PMID:29540678)
• Sec61 blockade induces proteostatic stress in the cytosol and the endoplasmic reticulum. (PMID:29915147)
• An mH segment in a nascent chain was cross-linked to the Sec61alpha pore-interior positions at TM5 and TM10, as well as the lateral gate. (PMID:30213864)
• Sec61alpha measurement has not an additional prognostic benefit for esophageal cancer patients. (PMID:31197453)
• Defective Sec61alpha1 underlies a novel cause of autosomal dominant severe congenital neutropenia. (PMID:32325141)
• Structure of the Inhibited State of the Sec Translocon. (PMID:32692975)
• An alternative pathway for membrane protein biogenesis at the endoplasmic reticulum. (PMID:34211117)
• Phenylbutyrate rescues the transport defect of the Sec61alpha mutations V67G and T185A for renin. (PMID:35064074)
• Comparative analysis of SEC61A1 mutant R236C in two patient-derived cellular platforms. (PMID:38664472)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sec61a1b	ENSDARG00000005675
danio_rerio	sec61a1a	ENSDARG00000021669
mus_musculus	Sec61a1	ENSMUSG00000030082
rattus_norvegicus	Sec61a1	ENSRNOG00000013743
drosophila_melanogaster	Sec61alpha	FBGN0086357
caenorhabditis_elegans		WBGENE00013311

Paralogs (1): SEC61A2 (ENSG00000065665)

Protein

Protein identifiers

Protein transport protein Sec61 subunit alpha isoform 1 — P61619 (reviewed: P61619)

All UniProt accessions (10): P61619, A0A8V8TMZ3, A0A8V8TMZ5, A0A8V8TN19, A0A8V8TN25, A0A8V8TNG8, A0A8V8TPD8, B3KNF6, B4DR61, C9JXC6

UniProt curated annotations — full annotation on UniProt →

Function. Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides. May cooperate with auxiliary protein SEC62, SEC63 and HSPA5/BiP to enable post-translational transport of small presecretory proteins. The SEC61 channel is also involved in ER membrane insertion of transmembrane proteins: it mediates membrane insertion of the first few transmembrane segments of proteins, while insertion of subsequent transmembrane regions of multi-pass membrane proteins is mediated by the multi-pass translocon (MPT) complex. The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER. Controls the passive efflux of calcium ions from the ER lumen to the cytosol through SEC61 channel, contributing to the maintenance of cellular calcium homeostasis. Plays a critical role in nephrogenesis, specifically at pronephros stage.

Subunit / interactions. The SEC61 channel-forming translocon complex consists of channel-forming core components SEC61A1, SEC61B and SEC61G and different auxiliary components such as SEC62 and SEC63. The SEC61 channel associates with the multi-pass translocon (MPT) complex.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in proximal and distal tubules in kidney (at protein level).

Disease relevance. Tubulointerstitial kidney disease, autosomal dominant 5 (ADTKD5) [MIM:617056] A form of autosomal dominant tubulointerstitial kidney disease, a genetically heterogeneous disorder characterized by slowly progressive loss of kidney function, bland urinary sediment, hyperuricemia, absent or mildly increased albuminuria, lack of severe hypertension during the early stages, and normal or small kidneys on ultrasound. Renal histology shows variable abnormalities including interstitial fibrosis with tubular atrophy, microcystic dilatation of the tubules, thickening of tubular basement membranes, medullary cysts, and secondary glomerulosclerotic or glomerulocystic changes with abnormal glomerular tufting. There is significant variability, as well as incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency, common variable, 15 (CVID15) [MIM:620670] An autosomal dominant immunologic disorder resulting in recurrent severe infections since early childhood or infancy, and characterized by hypogammaglobulinemia with antibody deficiencies of IgM, IgG, and IgA due to impaired plasma cell homeostasis, although other B cell subset numbers are normal. T and NK cells are also normal. CVID15 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Neutropenia, severe congenital, 11, autosomal dominant (SCN11) [MIM:620674] A form of severe congenital neutropenia, a disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l, and early onset of severe bacterial infections. SCN11 is characterized by the onset of recurrent infections, mainly bacterial, in early childhood. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SecY/SEC61-alpha family.

Isoforms (2)

UniProt ID	Names	Canonical?
P61619-1	1	yes
P61619-3	3

RefSeq proteins (3): NP_001387257, NP_001387258, NP_037468* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002208	SecY/SEC61-alpha	Family
IPR019561	Translocon_Sec61/SecY_plug_dom	Domain
IPR023201	SecY_dom_sf	Homologous_superfamily
IPR030659	SecY_CS	Conserved_site

Pfam: PF00344, PF10559

UniProt features (77 total): helix 22, topological domain 11, strand 11, transmembrane region 10, sequence conflict 9, turn 6, sequence variant 5, chain 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
8DNZ	ELECTRON MICROSCOPY	2.57
8DNY	ELECTRON MICROSCOPY	2.85
8DO0	ELECTRON MICROSCOPY	2.86
8DO2	ELECTRON MICROSCOPY	2.95
8DNX	ELECTRON MICROSCOPY	2.98
8DO1	ELECTRON MICROSCOPY	3.01
8DNV	ELECTRON MICROSCOPY	3.03
9D6L	ELECTRON MICROSCOPY	3.1
9N9J	ELECTRON MICROSCOPY	3.2
8DO3	ELECTRON MICROSCOPY	3.22
8OJ0	ELECTRON MICROSCOPY	3.3
8DNW	ELECTRON MICROSCOPY	3.4
6W6L	ELECTRON MICROSCOPY	3.84
9YGY	ELECTRON MICROSCOPY	4.1
8B6L	ELECTRON MICROSCOPY	7.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61619-F1	73.19	0.00

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
344	reduces cotranslational translocation of apln precursor/preproapelin.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1799339	SRP-dependent cotranslational protein targeting to membrane
R-HSA-1236975	Antigen processing-Cross presentation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 395 (showing top): YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, MODULE_149, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN

GO Biological Process (12): cotranslational protein targeting to membrane (GO:0006613), SRP-dependent cotranslational protein targeting to membrane (GO:0006614), SRP-dependent cotranslational protein targeting to membrane, translocation (GO:0006616), post-translational protein targeting to endoplasmic reticulum membrane (GO:0006620), endoplasmic reticulum organization (GO:0007029), post-translational protein targeting to membrane, translocation (GO:0031204), response to type II interferon (GO:0034341), pronephric nephron development (GO:0039019), protein targeting to ER (GO:0045047), protein insertion into ER membrane (GO:0045048), protein transport (GO:0015031), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (5): signal sequence receptor activity (GO:0005048), calcium channel activity (GO:0005262), transmembrane protein transporter activity (GO:0008320), ribosome binding (GO:0043022), protein binding (GO:0005515)

GO Cellular Component (4): Sec61 translocon complex (GO:0005784), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Antigen processing-Cross presentation	1
Translation	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein targeting to membrane	2
protein targeting to ER	2
intracellular protein transmembrane transport	2
translation	1
cotranslational protein targeting to membrane	1
SRP-dependent cotranslational protein targeting to membrane	1
organelle organization	1
endomembrane system organization	1
post-translational protein targeting to endoplasmic reticulum membrane	1
response to cytokine	1
innate immune response	1
pronephros development	1
nephron development	1
protein targeting	1
establishment of protein localization to endoplasmic reticulum	1
endoplasmic reticulum organization	1
protein localization to organelle	1
protein insertion into membrane	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
molecular_function	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
macromolecule transmembrane transporter activity	1
protein transmembrane transport	1
protein transporter activity	1
ribonucleoprotein complex binding	1
binding	1
translocon complex	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

164 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CANX	SEC61A1	psi-mi:“MI:0914”(association)	0.690
SEC61A1	CANX	psi-mi:“MI:0914”(association)	0.690
UPF3B	CASC3	psi-mi:“MI:0914”(association)	0.640
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
HSPA5	SEC61A1	psi-mi:“MI:0407”(direct interaction)	0.560
SEC61A1	HSPA5	psi-mi:“MI:0407”(direct interaction)	0.560
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
	XPO1	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
EGFR	SEC61A1	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (326): SEC61A1 (Affinity Capture-Western), SEC61A1 (Affinity Capture-RNA), SEC61A1 (Affinity Capture-RNA), SEC61A1 (Affinity Capture-MS), CLGN (Co-fractionation), MAGT1 (Co-fractionation), RPL13A (Co-fractionation), SEC61A1 (Co-fractionation), SEC61A1 (Co-fractionation), SEC61A1 (Co-fractionation), SEC61A1 (Co-fractionation), SEC61A1 (Co-fractionation), SEC61A1 (Co-fractionation), SEC61A1 (Co-fractionation), SEC61A1 (Co-fractionation)

ESM2 similar proteins: A1C3L4, A3CM55, A6QKE2, A8AWV0, B2ISB6, B9DJQ6, D3HAJ5, D8MEB8, F0P5S5, F2QF13, F6CFW7, F8LHW1, F8LR08, O51451, O52351, P10250, P28527, P28540, P38377, P38397, P46249, P51297, P61619, P61620, P61621, P79088, Q1XDJ1, Q2FUW2, Q2YZ90, Q3K059, Q4G351, Q4L9N9, Q54XK2, Q5EA68, Q5HCP4, Q5R5L5, Q6BN08, Q74L41, Q7A363, Q8AY31

Diamond homologs: O26134, O28377, O59442, P28541, P28542, P32915, P38377, P38379, P49978, P61619, P61620, P61621, P78979, P79088, Q25147, Q2KHX4, Q54XK2, Q5EA68, Q5NVM7, Q5R5L5, Q60175, Q6BN08, Q6CPY9, Q6FRY3, Q752H7, Q7T277, Q7T278, Q870W0, Q8AY31, Q8AY32, Q8AY33, Q8AY34, Q8AY35, Q8AY36, Q8U019, Q90YL4, Q90ZM2, Q96TW8, Q977V3, Q98SN8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SEC61A1	“form complex”	“SEC61 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 168 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
SRP-dependent cotranslational protein targeting to membrane	13	10.9×	1e-07
Dengue Virus Attachment and Entry	5	10.9×	2e-03
SARS-CoV-1-host interactions	7	10.3×	2e-04
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	12	9.8×	1e-06
Nonsense-Mediated Decay (NMD)	5	9.8×	3e-03
Peptide chain elongation	9	9.6×	4e-05
Viral mRNA Translation	9	9.6×	4e-05
Constitutive Signaling by Aberrant PI3K in Cancer	9	9.6×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	7	21.7×	8e-06
cell surface receptor protein tyrosine kinase signaling pathway	14	17.9×	4e-11
cytoplasmic translation	10	13.6×	1e-06
mRNA export from nucleus	5	10.9×	8e-03
protein autophosphorylation	9	9.6×	9e-05
phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	9.3×	4e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	14	8.1×	1e-06
ERAD pathway	6	8.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	64
Likely benign	104
Benign	19

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1686175	NM_013336.4(SEC61A1):c.186C>A (p.Phe62Leu)	Pathogenic
253146	NM_013336.4(SEC61A1):c.553A>G (p.Thr185Ala)	Pathogenic
253147	NM_013336.4(SEC61A1):c.200T>G (p.Val67Gly)	Pathogenic
2686029	NM_013336.4(SEC61A1):c.275A>G (p.Gln92Arg)	Pathogenic
1804890	NM_013336.4(SEC61A1):c.265C>T (p.Leu89Phe)	Likely pathogenic
549498	NM_013336.4(SEC61A1):c.254T>A (p.Val85Asp)	Likely pathogenic

SpliceAI

1299 predictions. Top by Δscore:

Variant	Effect	Δscore
3:128052556:GCAA:G	donor_gain	1.0000
3:128052560:G:GG	donor_gain	1.0000
3:128052828:A:AG	acceptor_gain	1.0000
3:128052829:T:G	acceptor_gain	1.0000
3:128052831:A:AG	acceptor_gain	1.0000
3:128052832:A:G	acceptor_gain	1.0000
3:128052833:A:AG	acceptor_gain	1.0000
3:128052834:G:GG	acceptor_gain	1.0000
3:128055514:A:AG	acceptor_gain	1.0000
3:128055515:G:GG	acceptor_gain	1.0000
3:128055579:CAGGT:C	donor_loss	1.0000
3:128055582:G:T	donor_loss	1.0000
3:128055583:T:A	donor_loss	1.0000
3:128055749:GAG:G	donor_gain	1.0000
3:128056697:C:A	acceptor_gain	1.0000
3:128056704:TCAA:T	acceptor_loss	1.0000
3:128056706:A:AG	acceptor_gain	1.0000
3:128056706:AAG:A	acceptor_gain	1.0000
3:128056707:A:G	acceptor_gain	1.0000
3:128056708:G:C	acceptor_loss	1.0000
3:128056708:G:GG	acceptor_gain	1.0000
3:128056708:GGC:G	acceptor_gain	1.0000
3:128056708:GGCAC:G	acceptor_gain	1.0000
3:128056836:AAAGT:A	donor_gain	1.0000
3:128056837:AAGT:A	donor_gain	1.0000
3:128056839:GT:G	donor_gain	1.0000
3:128056841:G:C	donor_loss	1.0000
3:128056841:G:GG	donor_gain	1.0000
3:128056842:T:A	donor_loss	1.0000
3:128056849:GATT:G	donor_gain	1.0000

AlphaMissense

3085 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:128055556:T:A	L39H	1.000
3:128055556:T:C	L39P	1.000
3:128055564:T:C	F42L	1.000
3:128055566:C:A	F42L	1.000
3:128055566:C:G	F42L	1.000
3:128055728:G:C	R66T	1.000
3:128055728:G:T	R66I	1.000
3:128055740:C:A	A70D	1.000
3:128055742:T:C	S71P	1.000
3:128055743:C:T	S71F	1.000
3:128056712:C:T	T75I	1.000
3:128056726:G:A	G80R	1.000
3:128056726:G:C	G80R	1.000
3:128056726:G:T	G80W	1.000
3:128056727:G:A	G80E	1.000
3:128056727:G:T	G80V	1.000
3:128056736:C:A	P83H	1.000
3:128056742:T:A	V85D	1.000
3:128056754:T:C	L89P	1.000
3:128056766:T:C	L93P	1.000
3:128060108:G:A	G120D	1.000
3:128060509:T:C	L155P	1.000
3:128060520:G:C	G159R	1.000
3:128060548:T:C	L168P	1.000
3:128060565:G:C	G174R	1.000
3:128060566:G:A	G174D	1.000
3:128060587:T:A	L181H	1.000
3:128060587:T:C	L181P	1.000
3:128060589:T:C	F182L	1.000
3:128060590:T:C	F182S	1.000

dbSNP variants (sampled 300 via entrez): RS1000125550 (3:128062365 CAG>C), RS1000185501 (3:128057158 T>A), RS1000320598 (3:128057148 G>A), RS1000384694 (3:128057594 C>G,T), RS1000667335 (3:128063900 C>T), RS1000735966 (3:128063638 A>G), RS1000750941 (3:128070453 A>T), RS1000764286 (3:128069738 G>A,T), RS1000826346 (3:128050237 A>G), RS1000898114 (3:128063441 A>C,G), RS1001315700 (3:128058601 C>T), RS1001427693 (3:128051630 C>G), RS1001604048 (3:128057963 T>A), RS1001608570 (3:128051932 C>A,G), RS1001676017 (3:128070731 G>A)

Disease associations

OMIM: gene MIM:609213 | disease phenotypes: MIM:174050, MIM:617056, MIM:620674, MIM:620670

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperuricemic nephropathy, familial juvenile type 4	Strong	Autosomal dominant
immunodeficiency, common variable, 15	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
SEC61A1 deficiency	Moderate	AD

Mondo (5): autosomal dominant polycystic liver disease (MONDO:0000447), hyperuricemic nephropathy, familial juvenile type 4 (MONDO:0014891), neutropenia, severe congenital, 11, autosomal dominant (MONDO:0958017), (MONDO:0014866), immunodeficiency, common variable, 15 (MONDO:0958013)

Orphanet (3): Isolated polycystic liver disease (Orphanet:2924), DNAJB2-related Charcot-Marie-Tooth disease type 2 (Orphanet:443950), Common variable immunodeficiency phenotype due to SEC61A1 deficiency (Orphanet:697417)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000089	Renal hypoplasia
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000107	Renal cyst
HP:0000110	Renal dysplasia
HP:0000112	Nephropathy
HP:0000230	Gingivitis
HP:0000278	Retrognathia
HP:0000325	Triangular face
HP:0000403	Recurrent otitis media
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0001058	Poor wound healing
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001562	Oligohydramnios
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001882	Decreased total leukocyte count
HP:0001903	Anemia
HP:0001919	Acute kidney injury
HP:0001997	Gout
HP:0002090	Pneumonia
HP:0002149	Hyperuricemia
HP:0002153	Hyperkalemia
HP:0002572	Episodic vomiting
HP:0002719	Recurrent infections
HP:0002720	Decreased circulating IgA concentration
HP:0002783	Recurrent lower respiratory tract infections

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004899_7	Gestational age at birth (maternal effect)	9.000000e-15
GCST007611_8	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	9.000000e-10
GCST007656_11	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005112	gestational age
EFO:0005939	parental genotype effect measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725113 (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
7.29	Kd	50.78	nM	CHEMBL5653589
7.29	ED50	50.78	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 8 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149367: Binding affinity to human SEC61A1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0508	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	4
Acetaminophen	affects response to substance, increases expression	3
sodium arsenite	increases expression	2
Air Pollutants	increases abundance, increases expression	2
Cisplatin	decreases expression, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Tunicamycin	increases expression	2
Valproic Acid	increases expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases methylation, increases abundance, increases expression	2
Thapsigargin	increases transport, increases expression, increases response to substance	2
bisphenol F	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
bisphenol A	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652409	Binding	Binding affinity to human SEC61A1 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)

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

Trial	Phase	Status	Title
NCT01157858	PHASE2	COMPLETED	Everolimus and LongActing Octreotide Trial in Polycystic Livers
NCT01670110	PHASE2	COMPLETED	Pasireotide LAR in Severe Polycystic Liver Disease
NCT02021110	PHASE2	COMPLETED	Ursodeoxycholic Acid as Treatment for Polycystic Liver Disease
NCT05478083	PHASE2	RECRUITING	A GnRH Agonist IN Pre-menopausal Women STudy to Treat Severe Polycystic Liver Disease
NCT00426153	PHASE2/PHASE3	COMPLETED	Octreotide in Severe Polycystic Liver Disease
NCT00565097	PHASE2/PHASE3	COMPLETED	Lanreotide as Treatment of Polycystic Livers
NCT00771888	PHASE2/PHASE3	UNKNOWN	Open-Label Extension of LOCKCYST Trial
NCT01315795	PHASE2/PHASE3	COMPLETED	Lanreotide Autogel in the Treatment of Symptomatic Polycystic Liver Disease
NCT05281328	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Assess the Efficacy and Safety of Octreotide Subcutaneous Depot in Patients With PLD
NCT00934791	Not specified	TERMINATED	Polycystic Liver Disease in Kidney Transplant
NCT01354405	Not specified	COMPLETED	Somatostatin Analogues as a Volume Reducing Treatment of Polycystic Livers (RESOLVE)
NCT02173080	Not specified	COMPLETED	Development and Assessment of The Polycystic Liver Disease Questionnaire (PLD-Q).
NCT03960710	Not specified	UNKNOWN	Automatic Segmentation of Polycystic Liver
NCT04111692	Not specified	RECRUITING	A Prospective Observational Study of Foam Sclerotherapy .
NCT04645251	Not specified	RECRUITING	Polycystic Liver Disease Registry (UK)
NCT05215964	Not specified	UNKNOWN	The Association Between Skeletal Muscle Mass and Severity of Polycystic Liver Disease and Polycystic Kidney Disease
NCT05500157	Not specified	UNKNOWN	Assessment of Treatment With Laparoscopic Fenestration or Aspiration Sclerotherapy for Large Symptomatic Hepatic Cysts