SIL1

Summary

SIL1 (SIL1 nucleotide exchange factor, HGNC:24624) is a protein-coding gene on chromosome 5q31.2, encoding Nucleotide exchange factor SIL1 (Q9H173). Required for protein translocation and folding in the endoplasmic reticulum (ER).

This gene encodes a resident endoplasmic reticulum (ER), N-linked glycoprotein with an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. This protein functions as a nucleotide exchange factor for another unfolded protein response protein. Mutations in this gene have been associated with Marinesco-Sjogren syndrome. Alternate transcriptional splice variants have been characterized.

Source: NCBI Gene 64374 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Marinesco-Sjogren syndrome (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 421 total — 27 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 66
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_022464

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24624
Approved symbol	SIL1
Name	SIL1 nucleotide exchange factor
Location	5q31.2
Locus type	gene with protein product
Status	Approved
Aliases	BAP, ULG5
Ensembl gene	ENSG00000120725
Ensembl biotype	protein_coding
OMIM	608005
Entrez	64374

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 36 protein_coding, 6 protein_coding_CDS_not_defined

ENST00000265195, ENST00000394817, ENST00000440765, ENST00000503732, ENST00000504666, ENST00000505353, ENST00000505830, ENST00000505945, ENST00000507002, ENST00000508639, ENST00000508744, ENST00000509400, ENST00000509534, ENST00000513453, ENST00000515008, ENST00000868000, ENST00000868001, ENST00000868002, ENST00000868003, ENST00000868004, ENST00000868005, ENST00000868006, ENST00000868007, ENST00000868008, ENST00000868009, ENST00000868010, ENST00000868011, ENST00000948133, ENST00000948134, ENST00000948135, ENST00000948136, ENST00000948137, ENST00000948138, ENST00000948139, ENST00000948140, ENST00000948141, ENST00000948142, ENST00000948143, ENST00000948144, ENST00000948145, ENST00000948148, ENST00000948149

RefSeq mRNA: 2 — MANE Select: NM_022464 NM_001037633, NM_022464

CCDS: CCDS4209

Canonical transcript exons

ENST00000394817 — 10 exons

Exon	Start	End
ENSE00001830788	138946724	138947473
ENSE00001916801	139198269	139198368
ENSE00003483151	139026801	139026992
ENSE00003493943	139050938	139051046
ENSE00003494644	138951171	138951335
ENSE00003496287	139127739	139127853
ENSE00003517704	139121035	139121173
ENSE00003522557	138951788	138951884
ENSE00003605974	139042620	139042719
ENSE00003631070	139021171	139021292

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.5223 / max 302.5122, expressed in 1824 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63728	18.5014	1812
63730	12.8609	1795
63729	3.0887	1527
63731	3.0255	1561
63736	0.0266	10
63727	0.0192	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	97.92	gold quality
body of pancreas	UBERON:0001150	96.70	gold quality
left testis	UBERON:0004533	96.55	gold quality
right testis	UBERON:0004534	96.43	gold quality
pancreas	UBERON:0001264	96.37	gold quality
stromal cell of endometrium	CL:0002255	96.36	gold quality
right adrenal gland	UBERON:0001233	96.24	gold quality
right adrenal gland cortex	UBERON:0035827	96.21	gold quality
left adrenal gland	UBERON:0001234	95.99	gold quality
left adrenal gland cortex	UBERON:0035825	95.79	gold quality
adrenal gland	UBERON:0002369	95.47	gold quality
right lobe of liver	UBERON:0001114	95.34	gold quality
sural nerve	UBERON:0015488	95.15	gold quality
adrenal cortex	UBERON:0001235	94.94	gold quality
calcaneal tendon	UBERON:0003701	94.63	gold quality
adenohypophysis	UBERON:0002196	94.59	gold quality
testis	UBERON:0000473	94.57	gold quality
colonic epithelium	UBERON:0000397	94.00	gold quality
adrenal tissue	UBERON:0018303	93.90	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.88	gold quality
apex of heart	UBERON:0002098	93.71	gold quality
pituitary gland	UBERON:0000007	93.42	gold quality
tendon of biceps brachii	UBERON:0008188	93.35	silver quality
liver	UBERON:0002107	93.14	gold quality
right lobe of thyroid gland	UBERON:0001119	93.01	gold quality
left lobe of thyroid gland	UBERON:0001120	92.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.87	gold quality
thyroid gland	UBERON:0002046	92.81	gold quality
ascending aorta	UBERON:0001496	92.66	gold quality
thoracic aorta	UBERON:0001515	92.58	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	88.23
E-CURD-122	yes	40.14
E-MTAB-8410	yes	23.65
E-ANND-3	yes	22.87
E-HCAD-13	yes	13.60
E-HCAD-1	yes	12.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting SIL1, 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-6814-5P	99.03	66.68	1273
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-6854-5P	96.77	65.96	848

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• BAP serves as a nucleotide exchange factor for BiP (PMID:12356756)
• Nine distinct mutations that would disrupt the SIL1 protein in individuals with Marinesco-Sjogren syndrome were identified. (PMID:16282977)
• Four Marinesco-Sjogren syndrome-associated loss-of-function mutations in SIL1 leading to disturbed SIL1-HSPA5 interaction and protein folding were identified. (PMID:16282978)
• A novel mutation in BAP/SIL1 gene causes Marinesco-Sjogren syndrome in an extended pedigree. (PMID:17026626)
• SIL1 mutation is associated with Marinesco-Sjogren syndrome (PMID:18285827)
• We sequenced the entire SIL1-coding region in 3 unrelated Japanese patients with classical MSS and identified a novel homozygous frameshift insertion mutation, 936_937insG, in exon 9 in all 3 patients. (PMID:18395226)
• data report two novel SIL1 missense mutations in two consanguineous Pakistani families affected with Marinesco-Sjogren syndrome (PMID:19471582)
• Some reported cases of Marinesco-Sjogren syndrome without base alterations in the SIL1 gene are caused by deletions rather than locus heterogeneity. (PMID:20111056)
• Interactions between Kar2p and its nucleotide exchange factors Sil1p and Lhs1p are mechanistically distinct (PMID:20430899)
• The patients described here manifested the cardinal features of Marinesco-Sjogren syndrome, but did not exhibit any mutation in the exons and flanking introns of the SIL1 gene. (PMID:22115007)
• the very C-terminal residues of SIL1 play a role in its structural integrity rather than its localization. (PMID:22219183)
• The clinical features and two novel SIL1 mutations of four Dutch patients with Marinesco-Sjogren syndrome are described (PMID:23062754)
• The study confirms the previous findings of mutations in SIL1 being the major cause of Marinesco-Sjogren syndrome. (PMID:24176978)
• The mutations prevent SIL1 from interacting with and regulating HSPA5, leading to abnormal neuronal morphology and migration. (PMID:24473200)
• This study demonistrated that SIL1 mutation in patient with ataxia telangiectasia (PMID:24631270)
• Two NEFs, Grp170 and Sil1, trigger toxin release from BiP to enable successful retrotranslocation and clarify the fate of the toxin after it disengages from BiP. (PMID:25877869)
• SIL1-depleted HEK293 cells are an appropriate model to identify proteins modulated by SIL1 expression level. (PMID:26468156)
• this case study is the first report on Chinese Marinesco-Sjogren syndrome (MSS) patients, MSS complicated by Dandy-Walker syndrome (DWS), and a nonstop mutation in SIL1; our findings imply the pathogenetic association between DWS and MSS (PMID:27106665)
• In a child with Marinesco-Sjogren syndrome it was found that a mutation in SIL1 affected the 5’ UTR, translation initiation site and the endoplasmic reticulum-targeting signal sequence. (PMID:27544240)
• single-molecule FRET experiments with mammalian proteins reveal that Bap affects the conformation of both BiP domains, including the lid subdomain, which is important for substrate binding (PMID:29323281)
• Findings indicate that SIL1 deficiency alters secretory transport, potentially contributing to the cellular pathology of Marinesco-Sjogren syndrome. (PMID:30293566)
• SIL1 deficiency causes degenerative changes of peripheral nerves and neuromuscular junctions in fish, mice and human. The data expand the spectrum of tissues affected by SIL1-loss and suggest that impaired neuromuscular transmission might be part of Marinesco-Sjogren Syndrome pathophysiology. (PMID:30468864)
• Nucleotide exchange factor SIL1 promotes the progress of breast cancer cells via regulating the cell cycle and apoptosis. (PMID:31791191)
• Proteomic Analysis of Marinesco-Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss. (PMID:34830330)
• Down-Regulation and Clinic-Pathological Correlation of SIK-1 and SIL-1-LNC in Non-Small Cell Lung Cancer Patients. (PMID:37116165)
• Exome sequencing revealed variants in SGCA and SIL1 genes underlying limb girdle muscular dystrophy and Marinesco-Sjogren syndrome patients. (PMID:39060875)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sil1	ENSDARG00000100564
mus_musculus	Sil1	ENSMUSG00000024357
rattus_norvegicus	Sil1	ENSRNOG00000019826
drosophila_melanogaster	Sil1	FBGN0039296

Paralogs (1): HSPBP1 (ENSG00000133265)

Protein

Protein identifiers

Nucleotide exchange factor SIL1 — Q9H173 (reviewed: Q9H173)

Alternative names: BiP-associated protein

All UniProt accessions (9): A0A0S2Z6B4, A0RZB6, D6R940, D6RAI3, D6RBP7, D6REA1, D6RG16, D6RIU8, Q9H173

UniProt curated annotations — full annotation on UniProt →

Function. Required for protein translocation and folding in the endoplasmic reticulum (ER). Functions as a nucleotide exchange factor for the ER lumenal chaperone HSPA5.

Subunit / interactions. Interacts with HSPA5.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Highly expressed in tissues which produce large amounts of secreted proteins such as kidney, liver and placenta. Also expressed in colon, heart, lung, ovary, pancreas, peripheral leukocyte, prostate, spleen and thymus. Expressed at low levels throughout the brain.

Post-translational modifications. N-glycosylated. Ubiquitinated by the CRL2(FEM1A) and CRL2(FEM1C) complexes, which recognize the -Lys-Xaa-Xaa-Arg C-degron at the C-terminus, leading to its degradation.

Disease relevance. Marinesco-Sjoegren syndrome (MSS) [MIM:248800] Autosomal recessive multisystem disorder which is characterized by cerebellar ataxia due to cerebellar atrophy, with Purkinje and granule cell loss and myopathy featuring marked muscle replacement with fat and connective tissue. Other cardinal features include bilateral cataracts, hypergonadotrophic hypogonadism and mild to severe intellectual disability. Skeletal abnormalities, short stature, dysarthria, strabismus and nystagmus are also frequent findings. Mutational inactivation of this protein may result in ER stress-induced cell death signaling or malfunctioning chaperone machineries that mishandle client proteins which are critical for the organs targeted in MSS. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SIL1 family.

RefSeq proteins (2): NP_001032722, NP_071909* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR013918	Nucleotide_exch_fac_Fes1	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR050693	SIL1/FES1/HPBP1	Family

Pfam: PF08609

UniProt features (8 total): glycosylation site 2, signal peptide 1, chain 1, region of interest 1, sequence variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6LEY	X-RAY DIFFRACTION	2.39
6LBN	X-RAY DIFFRACTION	2.9
8Q7R	ELECTRON MICROSCOPY	3.71
8PQL	ELECTRON MICROSCOPY	3.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H173-F1	81.68	0.56

Functional residue map

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

Glycosylation sites (2): 193, 236

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 258 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_PROTEIN_TARGETING, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_PROTEIN_MATURATION, KESHELAVA_MULTIPLE_DRUG_RESISTANCE, MODULE_480, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOBP_PROTEIN_FOLDING, GOBP_LOCALIZATION_WITHIN_MEMBRANE, MODULE_427, MODULE_192, chr5q31, GOCC_ENDOPLASMIC_RETICULUM_LUMEN, MARSON_BOUND_BY_FOXP3_STIMULATED

GO Biological Process (4): protein folding (GO:0006457), cotranslational protein targeting to membrane (GO:0006613), intracellular protein transport (GO:0006886), protein transport (GO:0015031)

GO Molecular Function (4): adenyl-nucleotide exchange factor activity (GO:0000774), identical protein binding (GO:0042802), obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular protein localization	2
cellular process	1
protein maturation	1
protein targeting to membrane	1
protein transport	1
intracellular transport	1
transport	1
establishment of protein localization	1
ATP binding	1
ADP binding	1
ATPase regulator activity	1
protein binding	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIL1	HYOU1	Q9Y4L1	959
SIL1	HSPA5	P11021	921
SIL1	DNAJB9	Q9UBS3	869
SIL1	SAR1B	Q9Y6B6	808
SIL1	SEC63	Q9UGP8	769
SIL1	HSPA4	P34932	754
SIL1	DNAJC3	Q13217	751
SIL1	HSP90B1	P14625	707
SIL1	AARS1	P49588	706
SIL1	SEC62	Q99442	684
SIL1	APTX	Q7Z2E3	598
SIL1	SETX	Q7Z333	577
SIL1	CTNNA1	P35221	572
SIL1	SEC61A1	P38378	541
SIL1	MATR3	P43243	537

IntAct

91 interactions, top by confidence:

A	B	Type	Score
SIL1	HSPA5	psi-mi:“MI:0914”(association)	0.740
HSPA5	SIL1	psi-mi:“MI:0915”(physical association)	0.740
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
VEGFD	ADAM9	psi-mi:“MI:0914”(association)	0.640
PPP2R2B	MYO9A	psi-mi:“MI:0914”(association)	0.640
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640
SIL1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	SIL1	psi-mi:“MI:0915”(physical association)	0.560
SGTB	SIL1	psi-mi:“MI:0915”(physical association)	0.560
PLXNA4	CRYZL1	psi-mi:“MI:0914”(association)	0.560
	PLOD2	psi-mi:“MI:0914”(association)	0.530
PDGFRL	ANKRD28	psi-mi:“MI:0914”(association)	0.530
C1QTNF9B	PLOD3	psi-mi:“MI:0914”(association)	0.530
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
TMEM106A	B4GALT3	psi-mi:“MI:0914”(association)	0.530
SIL1	SIL1	psi-mi:“MI:0915”(physical association)	0.400
AGA	SIL1	psi-mi:“MI:0915”(physical association)	0.400
SIL1	CCND3	psi-mi:“MI:0915”(physical association)	0.370
SIL1	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
Kat8	HCFC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (113): SIL1 (Two-hybrid), SIL1 (Affinity Capture-MS), SIL1 (Affinity Capture-MS), SIL1 (Co-fractionation), SIL1 (Co-fractionation), SIL1 (Proximity Label-MS), SIL1 (Affinity Capture-MS), HSPA5 (Affinity Capture-Western), CEP192 (Affinity Capture-MS), POC1A (Affinity Capture-MS), POC1B (Affinity Capture-MS), EDRF1 (Affinity Capture-MS), CNTNAP1 (Affinity Capture-MS), ERGIC2 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS)

ESM2 similar proteins: A2VD13, A6QP29, A7E3N7, B5DFG1, O75127, P54098, P54099, Q05AA6, Q13474, Q3SX05, Q3SZK4, Q3TYG6, Q3U0L2, Q3U5Q7, Q3URY6, Q3ZBK7, Q4R5Q4, Q53GS7, Q58CQ5, Q5R655, Q5RAS2, Q66H85, Q6NUQ4, Q6ZUX3, Q7YS91, Q80UU1, Q8BKF1, Q8BL74, Q8C0R7, Q8C1F5, Q8C2E4, Q8CJ00, Q8N4P6, Q8R322, Q8TE82, Q969Z0, Q96KN7, Q96MK2, Q99MQ3, Q9BQ95

Diamond homologs: A1DLW4, A2R4I6, A3LUY1, O43030, P0CN68, P0CN69, P38260, Q0CH70, Q0V4C4, Q1E3S4, Q2GXZ7, Q2U9E2, Q32KV6, Q4I624, Q4P7F2, Q4WDH3, Q59NN8, Q5AYT7, Q6BLA1, Q6C239, Q6CNM7, Q6FM01, Q6NUA7, Q6P6S4, Q75B89, Q9C239, Q9H173, Q08199, Q6CKV0, Q6FUS3, Q758U2, Q9EPK6, Q9VBV5, Q4R588, Q6BTV5, Q6IMX7, Q99P31, Q9NZL4, Q5A360, Q99158

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SIL1	“up-regulates activity”	HSPA5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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
Platelet degranulation	7	10.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	9
Uncertain significance	183
Likely benign	133
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028267	NM_022464.5(SIL1):c.1321G>T (p.Glu441Ter)	Pathogenic
1071735	NM_022464.5(SIL1):c.1117del (p.Leu373fs)	Pathogenic
1705920	NM_022464.5(SIL1):c.767+1G>A	Pathogenic
1711611	NM_022464.5(SIL1):c.646-2A>G	Pathogenic
1807098	NM_022464.5(SIL1):c.212dup (p.His71fs)	Pathogenic
1879632	NM_022464.5(SIL1):c.244+1G>A	Pathogenic
198254	NM_022464.5(SIL1):c.460C>T (p.Gln154Ter)	Pathogenic
2022678	NM_022464.5(SIL1):c.195_217del (p.Glu65fs)	Pathogenic
2054736	NM_022464.5(SIL1):c.936del (p.Leu313fs)	Pathogenic
2055572	NM_022464.5(SIL1):c.88del (p.Leu30fs)	Pathogenic
2080055	NM_022464.5(SIL1):c.1035del (p.Phe345fs)	Pathogenic
2622	NM_022464.5(SIL1):c.506_509dup (p.Asp170fs)	Pathogenic
2623	NM_022464.5(SIL1):c.645+1G>A	Pathogenic
2625	NM_022464.5(SIL1):c.331C>T (p.Arg111Ter)	Pathogenic
2626	NM_022464.5(SIL1):c.1029+1G>A	Pathogenic
2627	NM_022464.5(SIL1):c.1312C>T (p.Gln438Ter)	Pathogenic
2628	NM_022464.5(SIL1):c.1370T>C (p.Leu457Pro)	Pathogenic
2629	NM_022464.5(SIL1):c.936dup (p.Leu313fs)	Pathogenic
2630	NM_022464.5(SIL1):c.603_607del (p.Glu201fs)	Pathogenic
2631	NM_022464.5:c.454-6721_768-23561del	Pathogenic
2814077	NM_022464.5(SIL1):c.685dup (p.Gln229fs)	Pathogenic
285373	NM_022464.5(SIL1):c.1205del (p.Gly402fs)	Pathogenic
3246272	NC_000005.9:g.(?138356840)(138386755_?)del	Pathogenic
3652523	NM_022464.5(SIL1):c.1127_1128del (p.Gln376fs)	Pathogenic
4291789	NM_022464.5(SIL1):c.772_773insGACC (p.Pro258fs)	Pathogenic
631958	NM_022464.5(SIL1):c.947dup (p.Arg317fs)	Pathogenic
812923	NC_000005.10:g.139189727_139201554del	Pathogenic
1524458	NM_022464.5(SIL1):c.353+1G>T	Likely pathogenic
1675994	NM_022464.5(SIL1):c.453+1G>C	Likely pathogenic
2090726	NM_022464.5(SIL1):c.643_645+21del	Likely pathogenic

SpliceAI

4013 predictions. Top by Δscore:

Variant	Effect	Δscore
5:138947491:C:CT	acceptor_gain	1.0000
5:138947497:CCAGG:C	acceptor_gain	1.0000
5:138947498:C:CT	acceptor_gain	1.0000
5:138947498:C:T	acceptor_gain	1.0000
5:138947499:A:T	acceptor_gain	1.0000
5:138947506:G:GC	acceptor_gain	1.0000
5:138947512:G:C	acceptor_gain	1.0000
5:138947512:G:GC	acceptor_gain	1.0000
5:138951166:CTCA:C	donor_loss	1.0000
5:138951167:TCA:T	donor_loss	1.0000
5:138951168:CAC:C	donor_loss	1.0000
5:138951169:A:AC	donor_gain	1.0000
5:138951169:AC:A	donor_gain	1.0000
5:138951169:ACCTT:A	donor_gain	1.0000
5:138951170:C:CT	donor_gain	1.0000
5:138951170:C:G	donor_loss	1.0000
5:138951170:CC:C	donor_gain	1.0000
5:138951170:CCT:C	donor_gain	1.0000
5:138951170:CCTT:C	donor_gain	1.0000
5:138951170:CCTTC:C	donor_gain	1.0000
5:138951334:ACC:A	acceptor_loss	1.0000
5:138951336:CT:C	acceptor_loss	1.0000
5:138951783:CACA:C	donor_loss	1.0000
5:138951784:ACAC:A	donor_loss	1.0000
5:138951785:CA:C	donor_loss	1.0000
5:138951787:C:CT	donor_loss	1.0000
5:138951787:CCTT:C	donor_gain	1.0000
5:138951883:TG:T	acceptor_gain	1.0000
5:138951884:GC:G	acceptor_loss	1.0000
5:138951885:C:CC	acceptor_gain	1.0000

AlphaMissense

3006 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:139026820:A:G	L209P	0.999
5:139021180:G:T	A253D	0.998
5:139021186:C:T	G251D	0.998
5:139021273:A:G	L222P	0.998
5:139026808:A:T	V213D	0.998
5:139026883:A:G	L188P	0.998
5:138951292:G:T	A303D	0.997
5:138951325:G:T	A292E	0.997
5:139026806:G:C	H214D	0.997
5:139026820:A:T	L209H	0.997
5:139021181:C:G	A253P	0.996
5:139026829:A:G	L206P	0.996
5:138947371:A:G	W378R	0.995
5:138947371:A:T	W378R	0.995
5:138951184:A:G	L339P	0.995
5:138951834:A:G	L273P	0.995
5:139021187:C:G	G251R	0.995
5:139021198:G:T	A247E	0.995
5:139021234:A:G	L235P	0.995
5:138951265:C:T	G312E	0.994
5:138951280:A:G	F307S	0.994
5:138951322:A:G	L293P	0.994
5:139021282:G:T	A219E	0.994
5:138951873:A:T	V260D	0.993
5:139021184:C:G	A252P	0.993
5:139021192:A:T	V249E	0.993
5:138951313:A:G	L296P	0.992
5:139021189:A:G	L250P	0.992
5:139026829:A:C	L206R	0.992
5:139026829:A:T	L206H	0.992

dbSNP variants (sampled 300 via entrez): RS1000006295 (5:138988931 T>G), RS1000031959 (5:138981907 G>A), RS1000035574 (5:138988328 G>A,C,T), RS1000035654 (5:139092321 G>A,T), RS1000047095 (5:139087563 G>A), RS1000051573 (5:138965015 T>G), RS1000075543 (5:139128016 A>T), RS1000094920 (5:139079553 G>A), RS1000099042 (5:138958517 G>A,C), RS1000114106 (5:139188254 C>G,T), RS1000122262 (5:138949627 C>T), RS1000149810 (5:139115873 C>T), RS1000168050 (5:139141946 C>T), RS1000188368 (5:139008498 T>C,G), RS1000196013 (5:139132933 G>A)

Disease associations

OMIM: gene MIM:608005 | disease phenotypes: MIM:248800, MIM:300957, MIM:116200

GenCC curated gene-disease

Disease	Classification	Inheritance
Marinesco-Sjogren syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Marinesco-Sjogren syndrome	Definitive	AR

Mondo (7): Marinesco-Sjogren syndrome (MONDO:0009567), X-linked intellectual disability-short stature-overweight syndrome (MONDO:0010496), apraxia (MONDO:0000665), ptosis (MONDO:0000728), constipation disorder (MONDO:0002203), strabismus (MONDO:0003432), cataract (MONDO:0005129)

Orphanet (2): Marinesco-Sjögren syndrome (Orphanet:559), X-linked intellectual disability-short stature-overweight syndrome (Orphanet:457240)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000135	Hypogonadism
HP:0000252	Microcephaly
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000768	Pectus carinatum
HP:0000815	Hypergonadotropic hypogonadism
HP:0001156	Brachydactyly
HP:0001167	Abnormal finger morphology
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001321	Cerebellar hypoplasia
HP:0001328	Specific learning disability
HP:0001371	Flexion contracture
HP:0001385	Hip dysplasia
HP:0001460	Aplasia/Hypoplasia involving the skeletal musculature
HP:0001508	Failure to thrive
HP:0001618	Dysphonia
HP:0001763	Pes planus

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010725_68	Malaria	4.000000e-07
GCST010725_7	Malaria	2.000000e-06
GCST90000025_17	Appendicular lean mass	2.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001072	Apraxias	C10.597.606.881.350; C23.888.592.604.882.350; F01.700.875.350
D001763	Blepharoptosis	C11.338.204
D002386	Cataract	C11.510.245
D003248	Constipation	C23.888.821.150
D013285	Strabismus	C10.292.562.887; C11.590.810

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation, affects methylation	4
bisphenol A	affects expression, affects cotreatment, increases methylation, increases expression	3
Cisplatin	affects expression, decreases expression	2
Tunicamycin	increases expression	2
sodium bichromate	decreases expression	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
dinophysistoxin 1	decreases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
ICG 001	increases expression	1
bisphenol S	affects 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
Temozolomide	increases expression	1
Decitabine	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects methylation	1
Vehicle Emissions	increases reaction, affects expression	1
Carcinogens	decreases expression	1
Doxorubicin	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Isoniazid	decreases expression	1
Ivermectin	decreases expression	1
Mutagens	decreases expression	1
Thiram	decreases expression	1
Valproic Acid	increases expression	1
Zinc	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Metribolone	increases expression	1
Cyclosporine	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02887365	PHASE4	UNKNOWN	A Phase II Study of Tegafur-Uracil as Maintenance Chemotherapy in Patients With Stage II of Colon Cancer
NCT00793988	PHASE4	COMPLETED	Vibration-Assisted Anaesthesia
NCT01239498	PHASE4	UNKNOWN	Saline Injection - Assisted Anesthesia in Eyelid Surgery
NCT02761083	PHASE4	WITHDRAWN	PMCF-study Using Novosyn® Quick Suture Material in Ophthalmic Surgery
NCT04007276	PHASE4	NOT_YET_RECRUITING	The Effect of Lumify™ on Ocular Redness, Intraocular Pressure, and Eyelid Position in Glaucoma Patients
NCT07390578	PHASE4	NOT_YET_RECRUITING	Upneeq vs. Lumify Ptosis
NCT00149877	PHASE4	COMPLETED	Efficacy, Safety and Tolerability of Tegaserod in Patients With Chronic Constipation
NCT00153114	PHASE4	COMPLETED	PolyethyleneGlycol3350 Laxative vs Placebo in Constipated Children
NCT00153127	PHASE4	COMPLETED	Comparison of PolyethyleneGlycol and Placebo for Relief of Constipation From Constipating Medications
NCT00153140	PHASE4	COMPLETED	Polyethyleneglycol3350 vs Tegaserod in Treatment of Patients With Chronic Constipation
NCT00153153	PHASE4	COMPLETED	Extended Use of Polyethyleneglycol3350 Laxative in Constipated Patients
NCT00157638	PHASE4	COMPLETED	Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics
NCT00164125	PHASE4	COMPLETED	An Open Label Study of Chronic Polyethyleneglycol3350 Use in Constipated Patients
NCT00171522	PHASE4	COMPLETED	Preference of Tegaserod vs. PEG 3350 in Patients With Constipation
NCT00256984	PHASE4	COMPLETED	Study of Stapled Transanal Rectal Resection (STARR) Surgery in Refractory Constipation Associated With Obstructive Defecation Syndrome (ODS)
NCT00276354	PHASE4	COMPLETED	Study of Long-term Use of Forlax® in Elderly Patients With Chronic Constipation
NCT00286520	PHASE4	COMPLETED	Treatment of Fecal Incontinence and Constipation in Patients With Spinal Cord Injury
NCT00319670	PHASE4	COMPLETED	A Pilot Study of a New MiraLax® Dose Formulation For Use in Constipated Children
NCT00348634	PHASE4	TERMINATED	Effect of Tegaserod on Orocecal Transit in Elderly Chronic Constipation Patients
NCT00452335	PHASE4	COMPLETED	Safety and Efficacy of Lubiprostone in Pediatric Patients With Constipation
NCT00521872	PHASE4	COMPLETED	Stapled Trans Anal Rectal Resection (STARR) for Outlet Obstruction: Functional and Morphological Outcome
NCT00583609	PHASE4	COMPLETED	A Pilot Study of a New PEG3350 Dose Formulation For Use in Constipated Children
NCT00603681	PHASE4	COMPLETED	Comparison of PEG Solutions With and Without Electrolytes in the Treatment of Constipation
NCT00712543	PHASE4	COMPLETED	A Preference Study Comparing Kristalose® and Liquid Lactulose
NCT00763399	PHASE4	COMPLETED	Effect of Probiotics on Intestinal Bacterial Population and Immune Modulation
NCT00770432	PHASE4	COMPLETED	Study Comparing PEG 3350 Laxative to Placebo in the Treatment of Occasional Constipation (Study CL2007-12)(P08216)
NCT00799201	PHASE4	TERMINATED	Enteral Naloxone Versus a Traditional Bowel Regimen for the Prevention of Opioid Induced Constipation in Trauma Patients
NCT00844831	PHASE4	COMPLETED	Effects of Lubiprostone on Small Bowel and Colonic Bacteria: A Correlation Study With Segmental and Whole Gut Transit
NCT00949377	PHASE4	WITHDRAWN	Can Methylnaltrexone Safely Treat Opioid Related Constipation in the Emergency Department?
NCT01003249	PHASE4	TERMINATED	Dysfunctional Voiding and Lower Urinary Tract Symptoms With Baclofen
NCT01096290	PHASE4	TERMINATED	Comparison of Lubiprostone and Placebo for the Relief of Constipation From Constipating Medications
NCT01114997	PHASE4	TERMINATED	Effect of Lidocaine and Esmolol to Improve the Quality of Recovery
NCT01170039	PHASE4	COMPLETED	The Effectiveness of Lubiprostone in Constipated Diabetics
NCT01180725	PHASE4	COMPLETED	Investigation of Dried Plums in the Treatment of Adults With Constipation
NCT01189409	PHASE4	TERMINATED	Polyethylene Glycol (PEG) Versus Sennosides Study in Opioid-Induced Constipation in Cancer Patients
NCT01230840	PHASE4	COMPLETED	Effect of Wheat Dextrin on Calcium and Magnesium Absorption
NCT01236534	PHASE4	COMPLETED	Lubiprostone in Patients With Multiple Sclerosis Associated Constipation
NCT01267370	PHASE4	COMPLETED	Soy Polysaccharide Fiber for the Treatment of Chronic Constipation in Children: a Randomized, Double-blind Trial
NCT01333787	PHASE4	COMPLETED	Dietary Fiber Mixture in Constipated Pediatric Patients
NCT01424228	PHASE4	COMPLETED	Evaluation of Long-term Prucalopride Treatment With Chronic Constipation in Subjects Aged ≥ 18 Years