SEC63

Summary

SEC63 (SEC63 protein translocation regulator, HGNC:21082) is a protein-coding gene on chromosome 6q21, encoding Translocation protein SEC63 homolog (Q9UGP8). Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER). It is a selective cancer dependency (DepMap: 55.7% of cell lines).

The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encoded by this gene and SEC62 protein are found to be associated with ribosome-free SEC61 complex. It is speculated that Sec61-Sec62-Sec63 may perform post-translational protein translocation into the ER. The Sec61-Sec62-Sec63 complex might also perform the backward transport of ER proteins that are subject to the ubiquitin-proteasome-dependent degradation pathway. The encoded protein is an integral membrane protein located in the rough ER.

Source: NCBI Gene 11231 — RefSeq curated summary.

At a glance

• Gene–disease (curated): polycystic liver disease 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 564 total — 26 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 55.7% of screened cell lines
• MANE Select transcript: NM_007214

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21082
Approved symbol	SEC63
Name	SEC63 protein translocation regulator
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	SEC63L, PRO2507, ERdj2, DNAJC23
Ensembl gene	ENSG00000025796
Ensembl biotype	protein_coding
OMIM	608648
Entrez	11231

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 12 protein_coding, 6 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000369002, ENST00000429168, ENST00000446496, ENST00000459782, ENST00000460009, ENST00000465210, ENST00000466419, ENST00000473746, ENST00000484803, ENST00000489455, ENST00000884693, ENST00000884694, ENST00000884695, ENST00000884696, ENST00000884697, ENST00000938726, ENST00000938727, ENST00000938728, ENST00000955590, ENST00000955591

RefSeq mRNA: 1 — MANE Select: NM_007214 NM_007214

CCDS: CCDS5061

Canonical transcript exons

ENST00000369002 — 21 exons

Exon	Start	End
ENSE00000761651	107893482	107893655
ENSE00000761652	107893838	107893897
ENSE00000761655	107902844	107902998
ENSE00000761656	107904629	107904721
ENSE00000761657	107906448	107906580
ENSE00000761659	107908927	107909035
ENSE00000761660	107911346	107911396
ENSE00001018138	107882988	107883146
ENSE00001448579	107867756	107871847
ENSE00001869450	107957886	107958208
ENSE00003469692	107921797	107921909
ENSE00003526779	107924818	107924932
ENSE00003534480	107876564	107876662
ENSE00003553501	107881149	107881250
ENSE00003642274	107929415	107929514
ENSE00003654654	107901370	107901517
ENSE00003658466	107912716	107912774
ENSE00003671529	107913366	107913427
ENSE00003686262	107897649	107897731
ENSE00003686595	107872808	107872912
ENSE00003688803	107906683	107906777

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.6107 / max 475.9939, expressed in 1822 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74946	26.6229	1818
74945	7.2916	1728
74944	2.2454	1179
74943	1.6929	1015
74941	0.7579	367

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	99.78	gold quality
body of pancreas	UBERON:0001150	98.69	gold quality
parotid gland	UBERON:0001831	98.59	gold quality
stromal cell of endometrium	CL:0002255	97.66	gold quality
pancreas	UBERON:0001264	97.43	gold quality
bone marrow cell	CL:0002092	97.39	gold quality
ganglionic eminence	UBERON:0004023	97.25	gold quality
ventricular zone	UBERON:0003053	96.95	gold quality
left ovary	UBERON:0002119	96.88	gold quality
ovary	UBERON:0000992	96.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.80	gold quality
right ovary	UBERON:0002118	96.68	gold quality
calcaneal tendon	UBERON:0003701	96.48	gold quality
adrenal tissue	UBERON:0018303	96.46	gold quality
pericardium	UBERON:0002407	96.40	gold quality
adrenal gland	UBERON:0002369	96.27	gold quality
saliva-secreting gland	UBERON:0001044	96.25	gold quality
islet of Langerhans	UBERON:0000006	96.23	gold quality
cortical plate	UBERON:0005343	96.21	gold quality
left adrenal gland	UBERON:0001234	96.19	gold quality
cardia of stomach	UBERON:0001162	96.16	gold quality
right adrenal gland	UBERON:0001233	96.13	gold quality
right adrenal gland cortex	UBERON:0035827	96.08	gold quality
seminal vesicle	UBERON:0000998	96.06	gold quality
mucosa of stomach	UBERON:0001199	96.05	gold quality
adrenal cortex	UBERON:0001235	96.03	gold quality
blood vessel layer	UBERON:0004797	96.00	gold quality
left adrenal gland cortex	UBERON:0035825	95.94	gold quality
pylorus	UBERON:0001166	95.84	gold quality
left lobe of thyroid gland	UBERON:0001120	95.73	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-10	no	300.71
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

205 targeting SEC63, 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-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-144-3P	99.94	73.98	2698

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 55.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• Mutations in SEC63 cause autosomal dominant polycystic liver disease, suggesting a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicating noncilial ER proteins in human polycystic disease. (PMID:15133510)
• Sec63p expression was observed in all cyst epithelia regardless of mutational state. And, Cystogenesis in SEC63-associated PCLD occurs via a different mechanism. (PMID:18224332)
• identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non-sense mutations, and eight missense mutations (PMID:20095989)
• identified nucleoredoxin as an interaction partner of Sec63; characterized this interaction; Sec63 is linked to the Wnt signaling pathways and this interaction may be the reason why mutations in SEC63 can lead to polycystic liver disease (PMID:21251912)
• Silencing the human SEC63 genes inhibits transport of only a subset of signal-peptide-containing precursor proteins to endoplasmic reticulum. (PMID:22375059)
• Sec63 may perform a substrate-selective quantity control function during cotranslational endoplasmic reticulum import. (PMID:23166619)
• a SEC63 germline mutation may play a role in cyst formation in polycystic liver disease (PMID:23209713)
• Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62 (PMID:23287549)
• Results suggest that loss of PRKCSH and SEC63 leads to general defects in ciliogenesis, while quenching of the Wnt signaling cascade is cholangiocyte-restricted. (PMID:28973524)
• Identification of signal peptide features for substrate specificity in human Sec62/Sec63-dependent ER protein import. (PMID:32133789)
• A Molecular Mechanism for Turning Off IRE1alpha Signaling during Endoplasmic Reticulum Stress. (PMID:33378667)
• Integrative genetic, genomic and transcriptomic analysis of heat shock protein and nuclear hormone receptor gene associations with spontaneous preterm birth. (PMID:34429451)
• Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress. (PMID:37122003)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sec63	ENSDARG00000017740
mus_musculus	Sec63	ENSMUSG00000019802
rattus_norvegicus	Sec63	ENSRNOG00000000314
drosophila_melanogaster	Sec63	FBGN0035771
caenorhabditis_elegans	dnj-29	WBGENE00001047

Protein

Protein identifiers

Translocation protein SEC63 homolog — Q9UGP8 (reviewed: Q9UGP8)

Alternative names: DnaJ homolog subfamily C member 23

All UniProt accessions (4): A0A0S2Z5M1, A6PVC9, Q9UGP8, F8WB27

UniProt curated annotations — full annotation on UniProt →

Function. Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER). Proposed to play an auxiliary role in recognition of precursors with short and apolar signal peptides. May cooperate with SEC62 and HSPA5/BiP to facilitate targeting of small presecretory proteins into the SEC61 channel-forming translocon complex, triggering channel opening for polypeptide translocation to the ER lumen. Required for efficient PKD1/Polycystin-1 biogenesis and trafficking to the plasma membrane of the primary cilia.

Subunit / interactions. The ER translocon complex consists of channel-forming core components SEC61A1, SEC61B and SEC61G and different auxiliary components such as SEC62 and SEC63.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed, with high levels in the liver.

Disease relevance. Polycystic liver disease 2 with or without kidney cysts (PCLD2) [MIM:617004] An autosomal dominant hepatobiliary disease characterized by overgrowth of biliary epithelium and supportive connective tissue, resulting in multiple liver cysts. A subset of patients may develop kidney cysts that usually do not result in clinically significant renal disease. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_009145* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001623	DnaJ_domain	Domain
IPR004179	Sec63-dom	Domain
IPR014756	Ig_E-set	Homologous_superfamily
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036869	J_dom_sf	Homologous_superfamily

Pfam: PF00226, PF02889

UniProt features (34 total): sequence variant 11, topological domain 4, domain 3, compositionally biased region 3, modified residue 3, transmembrane region 3, region of interest 2, mutagenesis site 2, chain 1, coiled-coil region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UGP8-F1	77.71	0.42

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 (3): 537, 742, 748

Mutagenesis-validated functional residues (2):

Position	Phenotype
132	reduces cotranslational translocation of apln precursor/preproapelin.
735–760	reduces cotranslational translocation of apln precursor/preproapelin.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 304 (showing top): CREL_01, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, MORF_HDAC2, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, HEIDENBLAD_AMPLICON_8Q24_DN, MORF_RAF1, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, ONKEN_UVEAL_MELANOMA_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE

GO Biological Process (7): liver development (GO:0001889), protein targeting to membrane (GO:0006612), SRP-dependent cotranslational protein targeting to membrane (GO:0006614), post-translational protein targeting to endoplasmic reticulum membrane (GO:0006620), post-translational protein targeting to membrane, translocation (GO:0031204), nitrogen cycle metabolic process (GO:0071941), protein transport (GO:0015031)

GO Molecular Function (4): RNA binding (GO:0003723), transmembrane protein transporter activity (GO:0008320), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), membrane (GO:0016020), Sec62/Sec63 complex (GO:0031207), endoplasmic reticulum membrane (GO:0005789)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein targeting to ER	2
gland development	1
hepaticobiliary system development	1
protein targeting	1
establishment of protein localization to membrane	1
translation	1
cotranslational protein targeting to membrane	1
protein targeting to membrane	1
post-translational protein targeting to endoplasmic reticulum membrane	1
intracellular protein transmembrane transport	1
metabolic process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
nucleic acid binding	1
macromolecule transmembrane transporter activity	1
protein transmembrane transport	1
protein transporter activity	1
molecular transducer activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
endoplasmic reticulum Sec complex	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

2696 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEC63	SEC61A1	P38378	999
SEC63	SEC62	Q99442	999
SEC63	PRKCSH	P14314	978
SEC63	SEC61B	P38390	933
SEC63	SEC61G	P38384	922
SEC63	HYOU1	Q9Y4L1	771
SEC63	SIL1	Q9H173	769
SEC63	SNRNP200	O75643	729
SEC63	ALG8	Q9BVK2	687
SEC63	PKD1	P98161	676
SEC63	CALU	O43852	671
SEC63	DNAJC1	Q96KC8	656
SEC63	GANAB	Q14697	651
SEC63	TMEM214	Q6NUQ4	650
SEC63	EXD2	Q9NVH0	650

IntAct

174 interactions, top by confidence:

A	B	Type	Score
EXOC1	EXOC5	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
B3GAT3	GOLIM4	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
	DDX3X	psi-mi:“MI:0914”(association)	0.630
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
SEC63	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
Nxn	SEC63	psi-mi:“MI:0407”(direct interaction)	0.560
SEC63	Nxn	psi-mi:“MI:0407”(direct interaction)	0.560
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
	XPO1	psi-mi:“MI:0914”(association)	0.530
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
VAMP5	NBAS	psi-mi:“MI:0914”(association)	0.530
STK16	UNC119B	psi-mi:“MI:0914”(association)	0.530
BACC1	SMARCA5	psi-mi:“MI:0914”(association)	0.530
C3orf18	SPAG9	psi-mi:“MI:0914”(association)	0.530

BioGRID (485): SEC63 (Affinity Capture-MS), SEC63 (Affinity Capture-MS), SEC63 (Affinity Capture-MS), SEC63 (Affinity Capture-MS), SEC63 (Affinity Capture-MS), SEC63 (Affinity Capture-MS), ACADM (Co-fractionation), RPS5 (Co-fractionation), SEC63 (Co-fractionation), SEC63 (Co-fractionation), SEC63 (Co-fractionation), SEC63 (Co-fractionation), SEC63 (Affinity Capture-MS), SEC63 (Synthetic Growth Defect), SEC63 (Proximity Label-MS)

ESM2 similar proteins: A0A4X1TB62, A4VCH4, G3V7Q0, O14795, O35841, O43237, O70585, P23116, P48553, Q0P5J8, Q14152, Q15542, Q1JU68, Q3TLI0, Q3UHE1, Q4R5P6, Q5R660, Q5R7S4, Q5R7U7, Q5RE09, Q5RE70, Q5VSL9, Q5XI83, Q658Y4, Q68E01, Q6IQ26, Q6PAL8, Q6PDL0, Q6TEP1, Q6WKZ8, Q7SYD9, Q7TPD0, Q8BIK4, Q8BWQ6, Q8C079, Q8C092, Q8C9H6, Q8CBY8, Q8IWV8, Q8K400

Diamond homologs: A2PYH4, A2RUV5, A3MSA1, B6DMK2, D3Z4R1, E1BNG3, E7F8F4, E9PZJ8, F1LNJ2, F1LPQ2, F1NTD6, F4JAA5, O48534, O59025, O60072, O73946, O75643, P0DMI1, P32639, P35207, P51979, P53327, Q4JC00, Q54G57, Q54XN7, Q55CI8, Q58524, Q5D892, Q5H9U9, Q5JGV6, Q5R660, Q5UYM9, Q6P4T2, Q8IY21, Q8N3C0, Q8VHE0, Q974S1, Q9FNQ1, Q9HJX7, Q9P7T8

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
CSNK2A1	“up-regulates activity”	SEC63	phosphorylation
CSNK2B	“up-regulates activity”	SEC63	phosphorylation
SEC63	“up-regulates activity”	SEC62	binding
“SEC61 complex”	“up-regulates activity”	SEC63	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 219 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.

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	6	13.7×	3e-03
protein autophosphorylation	11	8.7×	8e-05
cell surface receptor protein tyrosine kinase signaling pathway	8	7.5×	5e-03
positive regulation of MAPK cascade	11	4.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	27
Uncertain significance	245
Likely benign	123
Benign	85

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048655	NM_007214.5(SEC63):c.1023C>A (p.Cys341Ter)	Pathogenic
1068902	NM_007214.5(SEC63):c.174G>A (p.Trp58Ter)	Pathogenic
1255557	NM_007214.5(SEC63):c.105G>A (p.Trp35Ter)	Pathogenic
1255563	NM_007214.5(SEC63):c.636G>A (p.Trp212Ter)	Pathogenic
1255576	NM_007214.5(SEC63):c.693_694dup (p.Thr232fs)	Pathogenic
1255599	NM_007214.5(SEC63):c.1577C>A (p.Ser526Ter)	Pathogenic
1255605	NM_007214.5(SEC63):c.1434_1435del (p.Met479fs)	Pathogenic
1255616	NM_007214.5(SEC63):c.422del (p.Met141fs)	Pathogenic
1255620	NM_007214.5(SEC63):c.1810A>T (p.Lys604Ter)	Pathogenic
1255623	NM_007214.5(SEC63):c.359_366del (p.Ile120fs)	Pathogenic
1255625	NM_007214.5(SEC63):c.1249G>T (p.Glu417Ter)	Pathogenic
1255626	NM_007214.5(SEC63):c.958G>T (p.Glu320Ter)	Pathogenic
1255630	NM_007214.5(SEC63):c.964del (p.Gln322fs)	Pathogenic
1255632	NM_007214.5(SEC63):c.1817_1821del (p.Asn606fs)	Pathogenic
1255635	NM_007214.5(SEC63):c.133C>T (p.Arg45Ter)	Pathogenic
1458698	NC_000006.11:g.(?108246002)(108250738_?)del	Pathogenic
167671	NM_007214.5(SEC63):c.109del (p.Arg37fs)	Pathogenic
1805345	NM_007214.5(SEC63):c.1094dup (p.Asn365fs)	Pathogenic
1945120	NM_007214.5(SEC63):c.1052_1053insGGTGGAAATAT (p.Glu352fs)	Pathogenic
2050280	NM_007214.5(SEC63):c.1111C>T (p.Gln371Ter)	Pathogenic
2167	NM_007214.5(SEC63):c.173G>A (p.Trp58Ter)	Pathogenic
2168	NM_007214.5(SEC63):c.442_443insA (p.Ala148fs)	Pathogenic
2169	NM_007214.5(SEC63):c.733+1G>A	Pathogenic
225125	NM_007214.5(SEC63):c.220del (p.Thr73_Val74insTer)	Pathogenic
3075701	NM_007214.5(SEC63):c.1331_1332del (p.Tyr444fs)	Pathogenic
522474	NM_007214.5(SEC63):c.514+1G>A	Pathogenic
1255547	NM_007214.5(SEC63):c.622G>C (p.Val208Leu)	Likely pathogenic
1255622	NM_007214.5(SEC63):c.359T>C (p.Ile120Thr)	Likely pathogenic
1255628	NM_007214.5(SEC63):c.1629G>C (p.Gln543His)	Likely pathogenic
1255629	NM_007214.5(SEC63):c.1124A>C (p.Gln375Pro)	Likely pathogenic

SpliceAI

3725 predictions. Top by Δscore:

Variant	Effect	Δscore
6:107871679:CA:C	donor_gain	1.0000
6:107871699:A:AC	donor_gain	1.0000
6:107871700:C:CC	donor_gain	1.0000
6:107871700:CTG:C	donor_gain	1.0000
6:107871706:A:AC	donor_gain	1.0000
6:107871706:AGT:A	donor_gain	1.0000
6:107871707:G:C	donor_gain	1.0000
6:107871723:T:TA	donor_gain	1.0000
6:107871735:T:TA	donor_gain	1.0000
6:107871844:CCAA:C	acceptor_gain	1.0000
6:107871845:CAAC:C	acceptor_gain	1.0000
6:107871848:C:CC	acceptor_gain	1.0000
6:107872802:TCTTA:T	donor_loss	1.0000
6:107872803:CTTA:C	donor_loss	1.0000
6:107872804:TTAC:T	donor_loss	1.0000
6:107872805:TA:T	donor_loss	1.0000
6:107872807:C:CG	donor_loss	1.0000
6:107872909:CTAC:C	acceptor_gain	1.0000
6:107872910:TAC:T	acceptor_gain	1.0000
6:107872913:C:CA	acceptor_loss	1.0000
6:107872913:C:CC	acceptor_gain	1.0000
6:107881248:CTC:C	acceptor_gain	1.0000
6:107881249:TCCT:T	acceptor_loss	1.0000
6:107881250:CCTAG:C	acceptor_loss	1.0000
6:107881252:T:G	acceptor_loss	1.0000
6:107882986:A:AC	donor_gain	1.0000
6:107882986:ACTG:A	donor_gain	1.0000
6:107882987:C:CT	donor_gain	1.0000
6:107882987:CT:C	donor_gain	1.0000
6:107882987:CTG:C	donor_gain	1.0000

AlphaMissense

5034 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:107876647:A:G	W651R	1.000
6:107876647:A:T	W651R	1.000
6:107881245:C:A	W613C	1.000
6:107881245:C:G	W613C	1.000
6:107909017:A:G	S215P	1.000
6:107911350:A:T	V207D	1.000
6:107911356:G:C	P205R	1.000
6:107911356:G:T	P205Q	1.000
6:107911357:G:A	P205S	1.000
6:107911359:A:C	L204R	1.000
6:107911359:A:T	L204H	1.000
6:107911374:G:T	A199E	1.000
6:107911380:C:T	G197E	1.000
6:107911381:C:G	G197R	1.000
6:107911381:C:T	G197R	1.000
6:107911384:A:G	Y196H	1.000
6:107911392:A:G	L193S	1.000
6:107911395:A:T	V192D	1.000
6:107912738:A:T	V184D	1.000
6:107912750:G:C	P180R	1.000
6:107912750:G:T	P180Q	1.000
6:107912751:G:A	P180S	1.000
6:107912751:G:T	P180T	1.000
6:107912753:A:C	L179R	1.000
6:107912753:A:G	L179P	1.000
6:107912753:A:T	L179Q	1.000
6:107912756:G:T	A178D	1.000
6:107912759:A:C	I177S	1.000
6:107912759:A:G	I177T	1.000
6:107912759:A:T	I177N	1.000

dbSNP variants (sampled 300 via entrez): RS1000005989 (6:107923009 T>A,G), RS1000045345 (6:107940928 T>C), RS1000050545 (6:107939770 A>G,T), RS1000130790 (6:107954629 G>A), RS1000141611 (6:107880819 G>A), RS1000214090 (6:107904946 CATA>C), RS1000221727 (6:107928743 C>G), RS1000230475 (6:107938565 T>TC), RS1000239077 (6:107956740 A>G), RS1000271941 (6:107887767 G>A), RS1000282035 (6:107874063 T>C), RS1000307127 (6:107917427 G>A), RS1000370006 (6:107921419 C>T), RS1000391299 (6:107937183 C>T), RS1000396527 (6:107956397 A>G)

Disease associations

OMIM: gene MIM:608648 | disease phenotypes: MIM:617004, MIM:174050, MIM:619267

GenCC curated gene-disease

Disease	Classification	Inheritance
polycystic liver disease 2	Definitive	Autosomal dominant
polycystic liver disease 1	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
polycystic liver disease 2	Definitive	AD

Mondo (6): polycystic liver disease 2 (MONDO:0014860), autosomal dominant polycystic liver disease (MONDO:0000447), biliary tract disorder (MONDO:0004868), polycystic liver disease 1 (MONDO:0008265), Glanzmann thrombasthenia 2 (MONDO:0031009), autosomal dominant medullary cystic kidney disease with or without hyperuricemia (MONDO:0008264)

Orphanet (2): Isolated polycystic liver disease (Orphanet:2924), Autosomal dominant tubulointerstitial kidney disease (Orphanet:34149)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000952	Jaundice
HP:0001407	Hepatic cysts
HP:0001654	Abnormal heart valve morphology
HP:0001732	Abnormality of the pancreas
HP:0002020	Gastroesophageal reflux
HP:0002027	Abdominal pain
HP:0002086	Abnormality of the respiratory system
HP:0002093	Respiratory insufficiency
HP:0002094	Dyspnea
HP:0002239	Gastrointestinal hemorrhage
HP:0002240	Hepatomegaly
HP:0002617	Vascular dilatation
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003270	Abdominal distention
HP:0003418	Back pain
HP:0003573	Increased total bilirubin
HP:0003581	Adult onset
HP:0004944	Dilatation of the cerebral artery
HP:0005562	Multiple renal cysts
HP:0006557	Polycystic liver disease
HP:0008872	Feeding difficulties in infancy
HP:0010741	Pedal edema
HP:0030948	Elevated gamma-glutamyltransferase level
HP:0033842	Early satiety

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010682_4	Graft survival time in renal transplantation (donor effect) x APOL1 genotype interaction	1.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005199	renal transplant outcome measurement
EFO:0007892	donor genotype effect measurement
EFO:0009324	APOL1 risk genotype carrier status

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001660	Biliary Tract Diseases	C06.130
C536137	Medullary cystic kidney disease 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067116 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.46	Kd	34.38	nM	CHEMBL5653589
7.46	ED50	34.38	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 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	2149371: Binding affinity to human SEC63 incubated for 45 mins by Kinobead based pull down assay	kd	0.0344	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
Cyclosporine	decreases expression, increases expression	4
bisphenol A	decreases expression, affects cotreatment, increases expression	2
Indomethacin	affects cotreatment, increases expression, decreases expression	2
Tunicamycin	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic	increases abundance, increases expression	1
Benztropine	increases expression	1
Caffeine	affects phosphorylation	1
Clozapine	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	decreases expression	1
Haloperidol	increases expression	1
Isoniazid	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	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
CHEMBL5652413	Binding	Binding affinity to human SEC63 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)

18 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
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
NCT04111692	Not specified	RECRUITING	A Prospective Observational Study of Foam Sclerotherapy .
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases