SBDS

Summary

SBDS (SBDS ribosome maturation factor, HGNC:19440) is a protein-coding gene on chromosome 7q11.21, encoding Ribosome maturation protein SBDS (Q9Y3A5). Required for the assembly of mature ribosomes and ribosome biogenesis. It is a common-essential gene (DepMap: required in 99.4% of cancer cell lines).

This gene encodes a highly conserved protein that plays an essential role in ribosome biogenesis. The encoded protein interacts with elongation factor-like GTPase 1 to disassociate eukaryotic initiation factor 6 from the late cytoplasmic pre-60S ribosomal subunit allowing assembly of the 80S subunit. Mutations within this gene are associated with the autosomal recessive disorder Shwachman-Bodian-Diamond syndrome. This gene has a closely linked pseudogene that is distally located.

Source: NCBI Gene 51119 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Shwachman-Diamond syndrome (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 390 total — 20 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 95
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_016038

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19440
Approved symbol	SBDS
Name	SBDS ribosome maturation factor
Location	7q11.21
Locus type	gene with protein product
Status	Approved
Aliases	CGI-97, FLJ10917, SDS, SWDS, SDO1
Ensembl gene	ENSG00000126524
Ensembl biotype	protein_coding
OMIM	607444
Entrez	51119

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 10 protein_coding, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000246868, ENST00000414306, ENST00000697860, ENST00000697861, ENST00000697862, ENST00000697863, ENST00000697864, ENST00000697865, ENST00000697866, ENST00000697867, ENST00000697868, ENST00000697869, ENST00000697897, ENST00000890817, ENST00000890818, ENST00000929093, ENST00000961547

RefSeq mRNA: 1 — MANE Select: NM_016038 NM_016038

CCDS: CCDS5537

Canonical transcript exons

ENST00000246868 — 5 exons

Exon	Start	End
ENSE00000909224	66994212	66994341
ENSE00000909225	66995290	66995586
ENSE00001017311	66987680	66988499
ENSE00003483847	66993217	66993417
ENSE00003550090	66991137	66991301

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 84.5358 / max 886.3918, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84232	81.9311	1828
204464	2.6047	1294

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	99.20	gold quality
tibial artery	UBERON:0007610	99.20	gold quality
calcaneal tendon	UBERON:0003701	99.19	gold quality
mucosa of stomach	UBERON:0001199	99.11	gold quality
aorta	UBERON:0000947	99.08	gold quality
right coronary artery	UBERON:0001625	99.01	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.99	gold quality
gastrocnemius	UBERON:0001388	98.93	gold quality
thoracic aorta	UBERON:0001515	98.93	gold quality
ascending aorta	UBERON:0001496	98.92	gold quality
muscle of leg	UBERON:0001383	98.89	gold quality
left coronary artery	UBERON:0001626	98.88	gold quality
skeletal muscle organ	UBERON:0014892	98.87	gold quality
descending thoracic aorta	UBERON:0002345	98.85	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.85	gold quality
right lung	UBERON:0002167	98.72	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.72	gold quality
lower esophagus	UBERON:0013473	98.71	gold quality
smooth muscle tissue	UBERON:0001135	98.69	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.66	gold quality
corpus callosum	UBERON:0002336	98.58	gold quality
substantia nigra	UBERON:0002038	98.57	gold quality
hypothalamus	UBERON:0001898	98.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.51	gold quality
right atrium auricular region	UBERON:0006631	98.50	gold quality
skeletal muscle tissue	UBERON:0001134	98.47	gold quality
nerve	UBERON:0001021	98.35	gold quality
tibial nerve	UBERON:0001323	98.35	gold quality
heart	UBERON:0000948	98.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.32	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	96.08
E-MTAB-10287	yes	48.62
E-HCAD-1	yes	29.77
E-GEOD-84465	yes	23.74
E-MTAB-8410	yes	20.49
E-MTAB-8142	yes	12.21
E-MTAB-10137	no	1392.54
E-MTAB-7606	no	1051.98
E-GEOD-83139	no	3.86
E-MTAB-9543	no	2.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting SBDS, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-4709-3P	98.88	68.04	1594

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Mutations in SBDS are associated with Shwachman-Diamond syndrome (PMID:12496757)
• Mutations in SBDS are associated with Shwachman-Diamond syndrome. (PMID:12496757)
• gene conversion mutations in SBDS are common to different ethnic groups, but they are not confined to a limited region of the gene (PMID:14749921)
• most, but not all, patients classified based on rigorous clinical criteria as having SDS had compound heterozygous mutations of SBDS; presence (or absence) of SBDS mutations may define subgroups of patients with SDS (PMID:15284109)
• patients with genetically proven SDS a genotype-phenotype relationship in SDS does not exist in clinical and hematologic terms (PMID:15769891)
• SBDS localization was cell-cycle dependent, with nucleolar localization during G1 and G2 and diffuse nuclear localization during S phase (PMID:15860664)
• analysis of phenotypic heterogeneity in Shwachman-Diamond syndrome patients carrying identical SBDS mutations (PMID:15942154)
• findings link Shwachman-Diamond syndrome to other bone marrow failure syndromes with defects in nucleolus-associated processes, including Diamond-Blackfan anemia, cartilage-hair hypoplasia, and dyskeratosis congenita (PMID:16529906)
• This is the first report of compound heterozygous missense mutations occurring in patients with SDS. Two novel missense mutations (c.362A > C in exon 3, and c.523C > T in exon 4) of the SBDS gene were identified in the patient. (PMID:17046571)
• A novel missense mutation (79TC) in exon 1 is reported in a girl with spondylometaphysial dysplasia, ecpanding the phenotype beyond Shwachman-Bodian-Diamond syndrome. (PMID:17400792)
• Mutations in the SBDS gene is associated with acquired aplastic anemia (PMID:17478638)
• SBDS is found in complexes containing the human Nip7 ortholog. (PMID:17643419)
• summary of documented SBDS mutations associated with Shwachman-Diamond syndrome (PMID:17916435)
• genetic analysis of SBDS and SH2D1A in Japanese children with AA (PMID:18024409)
• Mutations in the SBDS gene may therefore be the fifth identified molecular defect in CVID. (PMID:18190602)
• SBDS has pro-survival properties. Its inhibition results in accelerated apoptosis through the Fas pathway. (PMID:18268284)
• findings suggest that Shwachman-Diamond syndrome patients with mutations in the SBDS gene have a characteristic magnetic resonance imaging pattern of fat-replaced pancreas and that SBDS mutations are unlikely in patients without this pattern (PMID:18280855)
• SBDS loss results in abnormal accumulation of Fas at the plasma membrane, where it sensitizes the cells to stimulation by Fas ligand (PMID:19009351)
• We confirmed significant overexpression of osteoprotegerin and vascular endothelial growth factor-A by ELISA from supernatants of SBDS-depleted HeLa cells. (PMID:19014892)
• in all cases the i(7)(q10) carries a double dose of the c.258+2T>C. As the c.258+2T>C mutation still allows the production of some amount of normal protein, this may contribute to the low incidence of MDS/AML in this subset of SDS patients (PMID:19148133)
• SBDS is a multi-functional protein implicated in cellular stress responses. (PMID:19602484)
• analysis of SBDS expression and localization at the mitotic spindle in human myeloid progenitors (PMID:19759903)
• A novel mutation in a Fijian boy with Shwachman-Diamond syndrome. (PMID:19816210)
• Mutations of the Shwachman-Bodian-Diamond syndrome gene is not associated with refractory cytopenia. (PMID:19951977)
• determined the solution structure and backbone dynamics of the SBDS protein and describe its RNA binding site using NMR spectroscopy (PMID:20053358)
• SBDS-deficiency results in deregulation of reactive oxygen species leading to increased cell death and decreased cell growth in cancer. (PMID:20979173)
• the amount of mutated SBDS protein was decreased (PMID:21660439)
• SBDS full-length protein was localized in both the nucleus and cytoplasm, whereas patient-related truncated SBDS protein isoforms localize predominantly to the nucleus. (PMID:21695142)
• Erythropoiesis (in normal stem cells or in cells from Shwachman-Diamond syndrome patients) requires SBDS. Knockdown of SBDS leads to oxidative stress, to increased levels of ROS during erythroid differentiation, and disrupts ribosome biogenesis. (PMID:21963601)
• mesenchymal stromal cells from MDS patients show low gene and protein expression of DICER1 and DROSHA which are involved in the microRNA biogenesis, as well as their target gene SBDS. (PMID:22371183)
• We conclude that knockdown of SBDS leads to growth inhibition and defects in ribosome maturation (PMID:22997148)
• SBDS protein facilitates the release of eIF6, a factor that prevents ribosome joining. (PMID:23115272)
• Lack of mutation in exon 2 of sbds protein in acute myeloid leukemia suggests this subset is unlikely to have underlying sds (PMID:23189942)
• SBDS protein acts as a nucleotide exchange factor that stabilizes binding to GTP for human GTPase. (PMID:23831625)
• The interaction between EFL1 and SBDS was analyzed by size exclusion chromatography, gel shift assay, and isothermal titration calorimetry. The results showed that EFL1 interacted directly with SBDS. (PMID:24406167)
• Genetic variations in exon 2 of SBDS gene do not appear to be contributing to aplastic anemia in the north Indian population. (PMID:24636098)
• Association of EFL1 to SBDS did not modify the affinity for GTP but dramatically decreased that for GDP by increasing the dissociation rate of the nucleotide. (PMID:25991726)
• Association of Elongation Factor-like 1 (EFL1) GTPase to SBDS did not modify the affinity for GTP but dramatically decreased that for GDP by increasing the dissociation rate of the nucleotide. (PMID:25991726)
• Upon EFL1 binding, SBDS is repositioned around helix 69, thus facilitating a conformational switch in EFL1 that displaces eIF6 by competing for an overlapping binding site on the 60S ribosomal subunit. (PMID:26479198)
• SBDS function is specifically required for efficient translation re-initiation into the protein isoforms C/EBPalpha-p30 and C/EBPbeta-LIP, which is controlled by a single cis-regulatory upstream open reading frame (uORF) in the 5’ untranslated regions (5’ UTRs) of both mRNAs. (PMID:26762974)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sbds	ENSDARG00000027803
mus_musculus	Sbds	ENSMUSG00000025337
rattus_norvegicus	Sbds	ENSRNOG00000000888
drosophila_melanogaster	Sbds	FBGN0035714
caenorhabditis_elegans		WBGENE00021063

Protein

Protein identifiers

Ribosome maturation protein SBDS — Q9Y3A5 (reviewed: Q9Y3A5)

Alternative names: Shwachman-Bodian-Diamond syndrome protein

All UniProt accessions (10): Q9Y3A5, A0A0S2Z5I7, A0A8V8TLA5, A0A8V8TLC6, A0A8V8TLR8, A0A8V8TLS5, A0A8V8TMR6, A0A8V8TMS1, A0A8V8TN15, F8WE72

UniProt curated annotations — full annotation on UniProt →

Function. Required for the assembly of mature ribosomes and ribosome biogenesis. Together with EFL1, triggers the GTP-dependent release of EIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. Required for normal levels of protein synthesis. May play a role in cellular stress resistance. May play a role in cellular response to DNA damage. May play a role in cell proliferation.

Subunit / interactions. Associates with the 60S ribosomal subunit. Interacts with NPM1, RPA1 and PRKDC. May interact with NIP7. Found in a complex consisting of the 60S ribosomal subunit, SBDS and EFL1. Interacts with EFL1. Interacts with CLN3.

Subcellular location. Cytoplasm. Nucleus. Nucleolus. Nucleoplasm. Cytoskeleton. Spindle.

Tissue specificity. Widely expressed.

Disease relevance. Shwachman-Diamond syndrome 1 (SDS1) [MIM:260400] A form of Shwachman-Diamond syndrome, a disorder characterized by hematopoietic abnormalities, exocrine pancreatic dysfunction, and skeletal dysplasia. Intermittent or chronic neutropenia is the most common hematological manifestation, followed by anemia and thrombocytopenia. Some patients progress to bone marrow failure, myelodysplastic syndrome and malignant transformation, with acute myelogenous leukemia being the most common. Exocrine pancreatic dysfunction is generally the first presenting symptom in infancy. Short stature and metaphyseal dysplasia are the most frequent skeletal manifestations. SDS1 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SDO1/SBDS family.

RefSeq proteins (1): NP_057122* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002140	Sdo1/SBDS	Family
IPR018023	Ribosome_mat_SBDS_CS	Conserved_site
IPR018978	SDO1/SBDS_central	Domain
IPR019783	SDO1/SBDS_N	Domain
IPR036786	Ribosome_mat_SBDS_N_sf	Homologous_superfamily
IPR037188	Sdo1/SBDS_central_sf	Homologous_superfamily
IPR039100	Sdo1/SBDS-like	Family
IPR046928	SDO1/SBDS_C	Domain

Pfam: PF01172, PF09377, PF20268

UniProt features (46 total): strand 14, helix 9, sequence variant 8, sequence conflict 7, turn 4, initiator methionine 1, chain 1, mutagenesis site 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
5AN9	ELECTRON MICROSCOPY	3.3
6QKL	ELECTRON MICROSCOPY	3.3
5ANB	ELECTRON MICROSCOPY	4.1
5ANC	ELECTRON MICROSCOPY	4.2
2KDO	SOLUTION NMR
2L9N	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3A5-F1	73.97	0.04

Functional residue map

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

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (1):

Position	Phenotype
151	strongly reduced release of eif6 from pre-60s ribosome subunits.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 494 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RIBOSOME_BIOGENESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_CELL_CHEMOTAXIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GNF2_GSTM1, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GNF2_HPN, GOBP_GROWTH, GOBP_RIBOSOME_ASSEMBLY, MODULE_528, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (9): inner cell mass cell proliferation (GO:0001833), hematopoietic progenitor cell differentiation (GO:0002244), rRNA processing (GO:0006364), mitotic spindle organization (GO:0007052), bone mineralization (GO:0030282), leukocyte chemotaxis (GO:0030595), cytosolic ribosome assembly (GO:0042256), bone marrow development (GO:0048539), ribosome biogenesis (GO:0042254)

GO Molecular Function (5): RNA binding (GO:0003723), microtubule binding (GO:0008017), rRNA binding (GO:0019843), ribosome binding (GO:0043022), protein binding (GO:0005515)

GO Cellular Component (9): spindle pole (GO:0000922), acrosomal vesicle (GO:0001669), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), spindle (GO:0005819), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membraneless organelle	3
nuclear lumen	2
blastocyst growth	1
cell population proliferation	1
hemopoiesis	1
cell differentiation	1
RNA processing	1
rRNA metabolic process	1
ribosome biogenesis	1
mitotic cell cycle	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
ossification	1
biomineral tissue development	1
leukocyte migration	1
cell chemotaxis	1
ribosome assembly	1
tissue development	1
hematopoietic or lymphoid organ development	1
bone development	1
ribonucleoprotein complex biogenesis	1
nucleic acid binding	1
tubulin binding	1
RNA binding	1
ribonucleoprotein complex binding	1
binding	1
spindle	1
secretory granule	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
microtubule cytoskeleton	1

Protein interactions and networks

STRING

1794 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SBDS	EFL1	Q7Z2Z2	978
SBDS	RPL4	P36578	809
SBDS	TPST1	O60507	806
SBDS	EIF6	P56537	793
SBDS	DNAJC21	Q5F1R6	782
SBDS	TERT	O14746	684
SBDS	NIP7	Q9Y221	680
SBDS	CLN3	Q13286	679
SBDS	RPL11	P25121	640
SBDS	NMD3	Q96D46	628
SBDS	ELANE	P08246	619
SBDS	RPS19	P39019	615
SBDS	RPL5	P46777	608
SBDS	LSG1	Q9H089	607
SBDS	RPA1	P27694	594

IntAct

103 interactions, top by confidence:

A	B	Type	Score
MED17	MED19	psi-mi:“MI:0914”(association)	0.840
SBDS	EFL1	psi-mi:“MI:0407”(direct interaction)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EFL1	SBDS	psi-mi:“MI:0407”(direct interaction)	0.710
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
SBDS	KLHL6	psi-mi:“MI:0915”(physical association)	0.560
SPTBN5	SBDS	psi-mi:“MI:0915”(physical association)	0.540
SBDS	PLEC	psi-mi:“MI:0915”(physical association)	0.540
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
EGLN3	ACACA	psi-mi:“MI:0914”(association)	0.530
ATP6V0A1	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
SBDS	ACD	psi-mi:“MI:0915”(physical association)	0.510
SBDS	DNM1L	psi-mi:“MI:0914”(association)	0.480
TERF1	SBDS	psi-mi:“MI:0915”(physical association)	0.370
SBDS	TERF2IP	psi-mi:“MI:0915”(physical association)	0.370
POT1	SBDS	psi-mi:“MI:0915”(physical association)	0.370
Chaf1a	CBX5	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
GTF2E2	UBA6	psi-mi:“MI:0914”(association)	0.350
CAV3	SHTN1	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350
INTU	EED	psi-mi:“MI:0914”(association)	0.350
PAK4	SNRPE	psi-mi:“MI:0914”(association)	0.350

BioGRID (213): SBDS (Affinity Capture-MS), CARS (Co-fractionation), DDX17 (Co-fractionation), DDX5 (Co-fractionation), EFTUD1 (Co-fractionation), GORASP2 (Co-fractionation), PROSC (Co-fractionation), RPUSD2 (Co-fractionation), SBDS (Co-fractionation), SBDS (Co-fractionation), SBDS (Co-fractionation), SBDS (Co-fractionation), SBDS (Co-fractionation), SBDS (Co-fractionation), SBDS (Co-fractionation)

ESM2 similar proteins: A1D5Z0, A5D8M6, A5DG70, A5DWY7, A8XT37, B0XZZ2, B3RXR7, B6H2S6, B6QW35, B9WBR8, C4JWU3, C4Y8M4, C5DN84, C5DWG7, C5M6K8, C5PCH4, O14179, P20434, P34617, P42942, P48612, P50444, P70122, Q07953, Q23202, Q23670, Q3SWZ6, Q4WYV0, Q58DV0, Q59P53, Q5RAZ2, Q5RCE3, Q5RK30, Q5U567, Q5XIP1, Q5ZIY4, Q5ZK01, Q6CJ62, Q6CUH2, Q6DIT8

Diamond homologs: A5D8M6, O14179, O59220, P70122, Q07953, Q23202, Q3SWZ6, Q58011, Q5JIV0, Q5RAZ2, Q5RK30, Q5ZIY4, Q6DIT8, Q86KZ5, Q8SUL0, Q9V121, Q9Y3A5, Q9YCU5, O26781, O29759

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SBDS	up-regulates	EFL1	binding
SBDS	up-regulates	EIF6

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	23
Uncertain significance	207
Likely benign	99
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033391	NM_016038.2(SBDS):c.625-1delG	Pathogenic
1751823	NM_016038.4(SBDS):c.613C>T (p.Gln205Ter)	Pathogenic
21538	NM_016038.4(SBDS):c.258+1G>C	Pathogenic
21539	NM_016038.4(SBDS):c.297_300del (p.Glu99fs)	Pathogenic
21542	NM_016038.4(SBDS):c.624+1G>C	Pathogenic
2238012	NM_016038.4(SBDS):c.53_56dup (p.Met20fs)	Pathogenic
2498197	NC_000007.14:g.66971410_66990307del	Pathogenic
2498198	NM_016038.4(SBDS):c.258+347_459+223del	Pathogenic
265256	NM_016038.4(SBDS):c.120del (p.Ser41fs)	Pathogenic
2678592	NM_016038.4(SBDS):c.107del (p.Val36fs)	Pathogenic
2678598	NM_016038.4(SBDS):c.307_308del (p.Gln103fs)	Pathogenic
3195	NM_016038.4(SBDS):c.183_184delinsCT (p.Lys62Ter)	Pathogenic
3198	NM_016038.4(SBDS):c.101dup (p.Asn34fs)	Pathogenic
3382997	NM_016038.4(SBDS):c.160dup (p.His54fs)	Pathogenic
3776902	NM_016038.4(SBDS):c.129-2A>G	Pathogenic
3776903	NM_016038.4(SBDS):c.123del (p.Ser41fs)	Pathogenic
4076140	NM_016038.4(SBDS):c.356G>A (p.Cys119Tyr)	Pathogenic
807486	NM_016038.4(SBDS):c.18del (p.Thr7fs)	Pathogenic
929404	NM_016038.4(SBDS):c.460-1G>A	Pathogenic
985338	NM_016038.4(SBDS):c.373_374del (p.Lys125fs)	Pathogenic
1339526	NM_016038.4(SBDS):c.629G>A (p.Cys210Tyr)	Likely pathogenic
2431953	NM_016038.4(SBDS):c.478C>T (p.Gln160Ter)	Likely pathogenic
2433145	NM_016038.4(SBDS):c.452_453dup (p.Gln152fs)	Likely pathogenic
2678593	NM_016038.4(SBDS):c.523del (p.Arg175fs)	Likely pathogenic
2678596	NM_016038.4(SBDS):c.129-71_140del	Likely pathogenic
2678597	NM_016038.4(SBDS):c.115dup (p.Trp39fs)	Likely pathogenic
2678599	NM_016038.4(SBDS):c.129-2A>C	Likely pathogenic
2678600	NM_016038.4(SBDS):c.624+1G>A	Likely pathogenic
2678601	NM_016038.4(SBDS):c.101A>T (p.Asn34Ile)	Likely pathogenic
2678602	NM_016038.4(SBDS):c.128+1G>A	Likely pathogenic

SpliceAI

645 predictions. Top by Δscore:

Variant	Effect	Δscore
7:66988495:CATAC:C	acceptor_gain	1.0000
7:66991131:TCTTA:T	donor_loss	1.0000
7:66991132:CTTA:C	donor_loss	1.0000
7:66991133:TTA:T	donor_loss	1.0000
7:66991134:TAC:T	donor_loss	1.0000
7:66991135:A:AC	donor_gain	1.0000
7:66991135:A:AG	donor_loss	1.0000
7:66991136:C:CC	donor_gain	1.0000
7:66991136:CG:C	donor_gain	1.0000
7:66991136:CGA:C	donor_gain	1.0000
7:66991136:CGAT:C	donor_gain	1.0000
7:66991302:C:CA	acceptor_loss	1.0000
7:66991302:C:CC	acceptor_gain	1.0000
7:66991303:T:C	acceptor_loss	1.0000
7:66993213:TCA:T	donor_loss	1.0000
7:66993214:CACCT:C	donor_loss	1.0000
7:66993215:A:AC	donor_gain	1.0000
7:66993216:C:CC	donor_gain	1.0000
7:66993216:CCTG:C	donor_gain	1.0000
7:66993413:AAAAT:A	acceptor_gain	1.0000
7:66993414:AAAT:A	acceptor_gain	1.0000
7:66993415:AAT:A	acceptor_gain	1.0000
7:66993415:AATC:A	acceptor_loss	1.0000
7:66993415:AATCT:A	acceptor_gain	1.0000
7:66993416:AT:A	acceptor_gain	1.0000
7:66993416:ATCT:A	acceptor_gain	1.0000
7:66993418:C:CC	acceptor_gain	1.0000
7:66993426:A:AC	acceptor_gain	1.0000
7:66994208:CCA:C	donor_loss	1.0000
7:66994209:CAC:C	donor_loss	1.0000

AlphaMissense

1661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:66993376:T:A	R100S	1.000
7:66993376:T:G	R100S	1.000
7:66993404:C:T	G91E	1.000
7:66993405:C:G	G91R	1.000
7:66993405:C:T	G91R	1.000
7:66994299:A:C	F57L	1.000
7:66994299:A:T	F57L	1.000
7:66994301:A:G	F57L	1.000
7:66995325:G:C	C31W	1.000
7:66995329:G:T	A30D	1.000
7:66991300:G:T	A154D	0.999
7:66991301:C:G	A154P	0.999
7:66993223:T:A	K151N	0.999
7:66993223:T:G	K151N	0.999
7:66993270:C:G	A136P	0.999
7:66993321:A:G	C119R	0.999
7:66993330:C:G	A116P	0.999
7:66993332:A:T	V115E	0.999
7:66993341:G:T	A112E	0.999
7:66993342:C:G	A112P	0.999
7:66993377:C:G	R100T	0.999
7:66993404:C:A	G91V	0.999
7:66993413:A:C	L88W	0.999
7:66993413:A:G	L88S	0.999
7:66994258:A:G	L71P	0.999
7:66994273:G:T	A66D	0.999
7:66994282:C:T	G63D	0.999
7:66994283:C:G	G63R	0.999
7:66994291:A:T	V60D	0.999
7:66994303:A:T	V56E	0.999

dbSNP variants (sampled 300 via entrez): RS1000261392 (7:66995533 A>C,G), RS1001108019 (7:66991005 A>C), RS1001164433 (7:66991184 G>A), RS1001486715 (7:66996081 G>C), RS1001623627 (7:66996297 C>T), RS1001770698 (7:66995762 C>A,T), RS1003542051 (7:66992594 T>A), RS1003576090 (7:66987914 G>A,C), RS1003697890 (7:66996995 G>A,T), RS1003888173 (7:66997550 T>C,G), RS1004905281 (7:66993342 C>T), RS1005565290 (7:66995213 C>A,G,T), RS1005676193 (7:66989958 C>CA), RS1006241374 (7:66994962 A>G), RS1006312029 (7:66994365 C>G)

Disease associations

OMIM: gene MIM:607444 | disease phenotypes: MIM:260400, MIM:609135

GenCC curated gene-disease

Disease	Classification	Inheritance
Shwachman-Diamond syndrome	Definitive	Autosomal recessive
Shwachman-Diamond syndrome 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Shwachman-Diamond syndrome	Definitive	AR

Mondo (8): Shwachman-Diamond syndrome 1 (MONDO:0044204), aplastic anemia (MONDO:0015909), hereditary neoplastic syndrome (MONDO:0015356), Shwachman-Diamond syndrome (MONDO:0009833), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), enophthalmos (MONDO:0001210), aplastic anemia, susceptibility to (MONDO:0800414)

Orphanet (5): Rare aplastic anemia (Orphanet:182040), Idiopathic aplastic anemia (Orphanet:88), Inherited cancer-predisposing syndrome (Orphanet:140162), Shwachman-Diamond syndrome (Orphanet:811), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

95 total (30 of 95 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000155	Oral ulcer
HP:0000225	Gingival bleeding
HP:0000246	Sinusitis
HP:0000356	Abnormality of the outer ear
HP:0000365	Hearing impairment
HP:0000421	Epistaxis
HP:0000573	Retinal hemorrhage
HP:0000670	Carious teeth
HP:0000684	Delayed eruption of teeth
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
HP:0000736	Short attention span
HP:0000774	Narrow chest
HP:0000819	Diabetes mellitus
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000886	Deformed rib cage
HP:0000907	Anterior rib cupping
HP:0000920	Enlargement of the costochondral junction
HP:0000924	Abnormality of the skeletal system
HP:0000938	Osteopenia
HP:0000964	Eczematoid dermatitis
HP:0000988	Skin rash
HP:0001167	Abnormal finger morphology
HP:0001249	Intellectual disability
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001367	Abnormal joint morphology

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000741	Anemia, Aplastic	C15.378.050.085; C15.378.190.223.250
D015841	Enophthalmos	C11.675.319
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067367 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.08	Kd	829.8	nM	CHEMBL5653589
5.76	ED50	1719	nM	CHEMBL5653589

PubChem BioAssay actives

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

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149346: Binding affinity to human SBDS incubated for 45 mins by Kinobead based pull down assay	kd	0.8298	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	3
Arsenic	increases expression, decreases expression, affects cotreatment, increases abundance	3
bisphenol A	affects expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
cupric chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652388	Binding	Binding affinity to human SBDS 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

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0LP	GM28311	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01818726	PHASE4	TERMINATED	Safety and Efficacy of Exjade in the Treatment of Transfusion-dependent Iron Overload in Aplastic Anemia Patients
NCT01995331	PHASE4	UNKNOWN	Moderate-dose Cyclophosphamide for Childhood Acquired Aplastic Anemia
NCT01997372	PHASE4	UNKNOWN	Different Doses of Anti-thymocyte Globin to Treat Child Severe Aplastic Anemia
NCT02745717	PHASE4	COMPLETED	The Efficacy of Immunosuppressive Therapy Combined With Cord Blood Transfusion in Treatment of Severe Aplastic Anemia
NCT02838992	PHASE4	UNKNOWN	ATG Combined With Cyclophosphamide And Cord Blood Transfusion in Treating Patients With Severe Aplastic Anemia
NCT02875743	PHASE4	COMPLETED	King’s Invasive Aspergillosis Study II
NCT03176849	PHASE4	COMPLETED	A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 in Pediatric Patients Undergoing HSCT
NCT03896971	PHASE4	COMPLETED	Combination of Thrombopoietin Mimetic and Immunosuppressive Therapy in Aplastic Anaemia
NCT05996393	PHASE4	COMPLETED	CsA+ATG+AVA vs. CsA+AVA for the Treatment of Newly-diagnosed SAA in the Elderly
NCT06004791	PHASE4	UNKNOWN	A Prospective, Randomized, Controlled Study of rhTPO in Combination With Herombopag + CsA vs Herombopag + CsA for the Treatment of Primary TD-NSAA
NCT06009965	PHASE4	UNKNOWN	Efficacy of IST Combined With TPO-RA in the Treatment of AA and Establishment of a Recurrence Prediction System
NCT06069180	PHASE4	UNKNOWN	The Optimization of Conditioning Regimen for HLA Matched HSCT in SAA
NCT06424639	PHASE4	NOT_YET_RECRUITING	Luspatercept Plus CsA vs CsA for the Treatment of Newly Diagnosed Non-Transfusion-Dependent NSAA
NCT06426043	PHASE4	NOT_YET_RECRUITING	A Prospective Study on the Treatment of Recurrent/Refractory/Intolerable NSAA With Lusutrombopag
NCT06516484	PHASE4	NOT_YET_RECRUITING	Ropustin for Refractory Aplastic Anaemia After Radiotherapy - a Single-centre, Prospective, Open-label, Single-arm Study
NCT06525948	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of rhTPO in Combination With Cyclosporine Versus Cyclosporine Alone in the Treatment of TD-NSAA
NCT06535685	PHASE4	NOT_YET_RECRUITING	A Study of Romiplostim for the Treatment of Refractory Transfusion-dependent NSAA
NCT00004474	PHASE3	COMPLETED	Phase III Randomized Study of Cyclophosphamide With or Without Antithymocyte Globulin Before Bone Marrow Transplantation in Patients With Aplastic Anemia
NCT01145976	PHASE3	UNKNOWN	Comparison of Cy-Atg vs Flu-Atg for the Conditioning Therapy in Allo-HCT for Adult Aplastic Anemia
NCT01343680	PHASE3	TERMINATED	Trial of Two Central Venous Catheter (CVC) Flushing Schemes in Pediatric Hematology and Oncology Patients
NCT02099747	PHASE3	COMPLETED	hATG+CsA vs hATG+CsA+Eltrombopag for SAA
NCT03825744	PHASE3	COMPLETED	Hetrombopag or Placebo in Treatment-Naive Severe Aplastic Anemia
NCT04350606	PHASE3	COMPLETED	A Study to Assess Efficacy and Safety of PF-06462700 in Japanese Participants With Aplastic Anemia
NCT05600426	PHASE3	ACTIVE_NOT_RECRUITING	A Trial Comparing Unrelated Donor BMT With IST for Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT07001397	PHASE3	NOT_YET_RECRUITING	Study on the Short-term Efficacy and Safety of Recombinant Human Thrombopoietin Combined With Immunosuppressant Sequential Eltrombopag Ethanolamine Dry Suspension in the Treatment of SAA/TD-NSAA
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT00001962	PHASE2	TERMINATED	A Study to Determine Whether Therapy With Daclizumab Will Benefit Patients With Bone Marrow Failure
NCT00001964	PHASE2	COMPLETED	Combination Therapy of Severe Aplastic Anemia
NCT00004143	PHASE2	COMPLETED	Allogeneic Mixed Chimerism Stem Cell Transplant Using Campath for Hemoglobinopathies & Bone Marrow Failure Syndromes
NCT00004323	PHASE2	COMPLETED	Phase II Study of Bone Marrow Transplantation Using Related Donors in Patients With Aplastic Anemia
NCT00004464	PHASE2	COMPLETED	Study of High Dose Cyclophosphamide in Patients With Severe Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria
NCT00005935	PHASE2	COMPLETED	Mycophenolate Mofetil and Cyclosporine to Treat Relapsing Aplastic Anemia
NCT00053989	PHASE2	COMPLETED	NMA Allogeneic Hematopoietic Cell Transplant in Hematologic Cancer/Disorders
NCT00061360	PHASE2	COMPLETED	Improving Immunosuppressive Treatment for Patients With Severe Aplastic Anemia
NCT00065260	PHASE2	COMPLETED	Rabbit Antithymocyte Globulin Versus Campath-1H for Treating Severe Aplastic Anemia
NCT00343785	PHASE2	COMPLETED	Cyclophosphamide and Anti-thymocyte Globulin Followed By Methotrexate and Cyclosporine in Preventing Chronic Graft-Versus-Host Disease in Patients With Severe Aplastic Anemia Undergoing Donor Bone Marrow Transplant