SMARCD1

Summary

SMARCD1 (SWI/SNF related BAF chromatin remodeling complex subunit D1, HGNC:11106) is a protein-coding gene on chromosome 12q13.12, encoding SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (Q96GM5). Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). It is a selective cancer dependency (DepMap: 16.6% of cell lines).

The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI and has sequence similarity to the yeast Swp73 protein. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6602 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Coffin-Siris syndrome 11 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 112 total — 7 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 85
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 16.6% of screened cell lines
• MANE Select transcript: NM_003076

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11106
Approved symbol	SMARCD1
Name	SWI/SNF related BAF chromatin remodeling complex subunit D1
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	BAF60A, Rsc6p, CRACD1
Ensembl gene	ENSG00000066117
Ensembl biotype	protein_coding
OMIM	601735
Entrez	6602

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000381513, ENST00000394963, ENST00000547247, ENST00000547637, ENST00000548573, ENST00000549274, ENST00000549526, ENST00000550280, ENST00000550477, ENST00000551352, ENST00000551497, ENST00000551966, ENST00000879708, ENST00000915404, ENST00000915405, ENST00000915406, ENST00000915407, ENST00000915408, ENST00000915409

RefSeq mRNA: 2 — MANE Select: NM_003076 NM_003076, NM_139071

CCDS: CCDS8797, CCDS8798

Canonical transcript exons

ENST00000394963 — 13 exons

Exon	Start	End
ENSE00000837626	50090493	50090590
ENSE00000837631	50089884	50089985
ENSE00000837632	50088521	50088637
ENSE00001114645	50094437	50094572
ENSE00001162678	50090241	50090402
ENSE00001520154	50098947	50100707
ENSE00001803107	50096850	50096972
ENSE00002339316	50085342	50085546
ENSE00003513831	50086756	50086878
ENSE00003518719	50098714	50098815
ENSE00003593350	50086621	50086663
ENSE00003622570	50086161	50086348
ENSE00003658085	50087363	50087485

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 98.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.1074 / max 394.1826, expressed in 1822 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125406	26.7719	1797
125404	21.1627	1811
125405	1.0590	607
125408	0.1138	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	98.34	gold quality
ventricular zone	UBERON:0003053	97.51	gold quality
cortical plate	UBERON:0005343	97.38	gold quality
embryo	UBERON:0000922	95.13	gold quality
right lobe of thyroid gland	UBERON:0001119	95.00	gold quality
left lobe of thyroid gland	UBERON:0001120	94.70	gold quality
right ovary	UBERON:0002118	94.22	gold quality
cardia of stomach	UBERON:0001162	94.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.98	gold quality
body of uterus	UBERON:0009853	93.97	gold quality
metanephros cortex	UBERON:0010533	93.91	gold quality
tongue squamous epithelium	UBERON:0006919	93.90	gold quality
cerebellar hemisphere	UBERON:0002245	93.88	gold quality
left ovary	UBERON:0002119	93.83	gold quality
granulocyte	CL:0000094	93.82	gold quality
cerebellar cortex	UBERON:0002129	93.81	gold quality
right adrenal gland cortex	UBERON:0035827	93.78	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.77	gold quality
mucosa of stomach	UBERON:0001199	93.62	gold quality
thyroid gland	UBERON:0002046	93.55	gold quality
minor salivary gland	UBERON:0001830	93.50	gold quality
tibial nerve	UBERON:0001323	93.49	gold quality
lymph node	UBERON:0000029	93.48	gold quality
right adrenal gland	UBERON:0001233	93.38	gold quality
left testis	UBERON:0004533	93.22	gold quality
adrenal cortex	UBERON:0001235	93.21	gold quality
right testis	UBERON:0004534	93.14	gold quality
adenohypophysis	UBERON:0002196	93.11	gold quality
left adrenal gland	UBERON:0001234	93.08	gold quality
left adrenal gland cortex	UBERON:0035825	93.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RORA

miRNA regulators (miRDB)

190 targeting SMARCD1, 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-4283	100.00	66.42	2097
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4271	99.88	68.32	2244

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 16.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 20)

• In addition to previously identified BAF250, BAF60a may provide another critical and direct link between nuclear receptors and the BRG1 complex that is required for promoter recruitment and subsequent chromatin remodeling (PMID:12917342)
• SMARCD1/BAF60a is an androgen receptor cofactor that modulates TMPRSS2 expression (PMID:19762545)
• the association of EGFR, CALM3 and SMARCD1 gene polymorphisms with bone mineral density in white women, as conducted. (PMID:25396734)
• BAF57, BAF60a and SNF5 might act as novel pro-senescence factors in both normal and tumor human skin cells (PMID:28716547)
• miR-223 targets the expression of SWI/SNF complex protein SMARCD1 in atypical proliferative serous tumor and high-grade ovarian serous carcinomas. (PMID:29079174)
• MITF promoted BAF60A recruitment to melanocyte-specific promoters, and BAF60A was required to promote BRG1 recruitment and chromatin remodeling. (PMID:30515787)
• identification of a human neurodevelopmental disorder caused by SMARCD1 mutations (PMID:30879640)
• Modulation of chromatin remodeling proteins SMYD1 and SMARCD1 promotes contractile function of human pluripotent stem cell-derived ventricular cardiomyocyte in 3D-engineered cardiac tissues. (PMID:31097748)
• SMARCD1 is a transcriptional target of specific non-hotspot mutant p53 forms. (PMID:31637714)
• Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy. (PMID:31992292)
• hsa-miR-100-5p, an overexpressed miRNA in human ovarian endometriotic stromal cells, promotes invasion through attenuation of SMARCD1 expression. (PMID:32299427)
• Enhanced SMARCD1, a subunit of the SWI/SNF complex, promotes liver cancer growth through the mTOR pathway. (PMID:32514535)
• BAF60a Deficiency in Vascular Smooth Muscle Cells Prevents Abdominal Aortic Aneurysm by Reducing Inflammation and Extracellular Matrix Degradation. (PMID:32787523)
• NMR spectroscopy uncovers direct interaction between BAF60A and p53. (PMID:33168186)
• Smarcd1 Inhibits the Malignant Phenotypes of Human Glioblastoma Cells via Crosstalk with Notch1. (PMID:33190170)
• microRNA-99a-5p induces cellular senescence in gemcitabine-resistant bladder cancer by targeting SMARCD1. (PMID:35148461)
• Assembly and interaction of core subunits of BAF complexes and crystal study of the SMARCC1/SMARCE1 binary complex. (PMID:35158202)
• Integrated analysis reveals SMARCD1 is a potential biomarker and therapeutic target in skin cutaneous melanoma. (PMID:37401939)
• Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis. (PMID:37768825)
• SMARCD1 is an essential expression-restricted metastasis modifier. (PMID:39390150)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	smarcd1	ENSDARG00000019004
mus_musculus	Smarcd1	ENSMUSG00000023018
rattus_norvegicus	Smarcd1	ENSRNOG00000061572
drosophila_melanogaster	Bap60	FBGN0025463
caenorhabditis_elegans	swsn-2.2	WBGENE00015971
caenorhabditis_elegans		WBGENE00044072

Paralogs (2): SMARCD3 (ENSG00000082014), SMARCD2 (ENSG00000108604)

Protein

Protein identifiers

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 — Q96GM5 (reviewed: Q96GM5)

Alternative names: 60 kDa BRG-1/Brm-associated factor subunit A, BRG1-associated factor 60A, SWI/SNF complex 60 kDa subunit

All UniProt accessions (6): Q96GM5, F8VRQ4, F8VUB0, F8VW95, F8VZ70, H0YHV1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. Has a strong influence on vitamin D-mediated transcriptional activity from an enhancer vitamin D receptor element (VDRE). May be a link between mammalian SWI-SNF-like chromatin remodeling complexes and the vitamin D receptor (VDR) heterodimer. Mediates critical interactions between nuclear receptors and the BRG1/SMARCA4 chromatin-remodeling complex for transactivation. Interacts with AKIRIN2.

Subunit / interactions. Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B), and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific. Component of the BAF complex, which includes at least actin (ACTB), ARID1A/BAF250A, ARID1B/BAF250B, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57, SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C. In muscle cells, the BAF complex also contains DPF3. Component of neural progenitors-specific chromatin remodeling complex (npBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin. Component of the SWI/SNF-B (PBAF) chromatin remodeling complex, at least composed of SMARCA4/BRG1, SMARCB1/BAF47/SNF5, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, perhaps SMARCD3/BAF60C, SMARCC1/BAF155, SMARCC2/BAF170, PBRM1/BAF180, ARID2/BAF200 and actin (ACTB). Component of SWI/SNF (GBAF) subcomplex, which includes at least BICRA or BICRAL (mutually exclusive), BRD9, SS18, SMARCA2/BRM, SMARCA4/BRG1/BAF190A, ACTL6A/BAF53, SMARCC1/BAF155, and SMARCD1/BAF60A. Specifically interacts with the VDR heterodimer complex. Interacts with ESR1, NR3C1, NR1H4, PGR, SMARCA4, SMARCC1 and SMARCC2. Interacts with DPF2. Interacts with DPF3a (isoform 2 of DPF3/BAF45C) and with HDGFL2 in a DPF3a-dependent manner. Interacts with FOS, FOSB isoform 1 and 2, FOSL1 and FOSL2.

Subcellular location. Nucleus.

Tissue specificity. Expressed in all tissues tested, including brain, heart, kidney, liver, lung, muscle, pancreas and placenta.

Disease relevance. Coffin-Siris syndrome 11 (CSS11) [MIM:618779] A form of Coffin-Siris syndrome, a congenital multiple malformation syndrome with broad phenotypic and genetic variability. Cardinal features are intellectual disability, coarse facial features, hypertrichosis, and hypoplastic or absent fifth digit nails or phalanges. Additional features include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Sucking/feeding difficulties, poor growth, ophthalmologic abnormalities, hearing impairment, and spinal anomalies are common findings. CSS11 is an autosomal dominant form characterized by developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SMARCD family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96GM5-1	1	yes
Q96GM5-2	2

RefSeq proteins (2): NP_003067, NP_620710 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003121	SWIB_MDM2_domain	Domain
IPR019835	SWIB_domain	Domain
IPR036885	SWIB_MDM2_dom_sf	Homologous_superfamily
IPR038041	SMARCD1_SWIB_dom	Domain

Pfam: PF02201

UniProt features (40 total): helix 13, sequence variant 5, strand 5, modified residue 4, region of interest 4, turn 2, chain 1, domain 1, cross-link 1, splice variant 1, sequence conflict 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6LTH	ELECTRON MICROSCOPY	3
7VDV	ELECTRON MICROSCOPY	3.4
9RL4	ELECTRON MICROSCOPY	3.5
6LTJ	ELECTRON MICROSCOPY	3.7
9RN2	ELECTRON MICROSCOPY	4.1
9RMC	ELECTRON MICROSCOPY	4.2
7Y8R	ELECTRON MICROSCOPY	4.4
9RN1	ELECTRON MICROSCOPY	5.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96GM5-F1	78.37	0.51

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 (5): 203, 223, 101, 68, 88

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-8939243	RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
R-HSA-9824585	Regulation of MITF-M-dependent genes involved in pigmentation
R-HSA-9845323	Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)
R-HSA-9933937	Formation of the canonical BAF (cBAF) complex
R-HSA-9933939	Formation of the polybromo-BAF (pBAF) complex
R-HSA-9933946	Formation of the embryonic stem cell BAF (esBAF) complex
R-HSA-9933947	Formation of the non-canonical BAF (ncBAF) complex
R-HSA-9934037	Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)
R-HSA-1266738	Developmental Biology
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-9730414	MITF-M-regulated melanocyte development
R-HSA-9842860	Regulation of endogenous retroelements
R-HSA-9856651	MITF-M-dependent gene expression

MSigDB gene sets: 552 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELL_CYCLE_PHASE_TRANSITION, CREBP1_Q2, PID_REG_GR_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_REGULATION_OF_DNA_REPAIR, SP1_Q2_01, TTGGGAG_MIR150, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, PUJANA_CHEK2_PCC_NETWORK, GCM_PRKCG

GO Biological Process (19): nucleosome disassembly (GO:0006337), chromatin remodeling (GO:0006338), regulation of transcription by RNA polymerase II (GO:0006357), nervous system development (GO:0007399), positive regulation of cell population proliferation (GO:0008284), regulation of mitotic metaphase/anaphase transition (GO:0030071), positive regulation of T cell differentiation (GO:0045582), negative regulation of cell differentiation (GO:0045596), positive regulation of cell differentiation (GO:0045597), positive regulation of myoblast differentiation (GO:0045663), transcription initiation-coupled chromatin remodeling (GO:0045815), regulation of G0 to G1 transition (GO:0070316), cellular response to fatty acid (GO:0071398), positive regulation of stem cell population maintenance (GO:1902459), regulation of G1/S transition of mitotic cell cycle (GO:2000045), positive regulation of double-strand break repair (GO:2000781), regulation of nucleotide-excision repair (GO:2000819), chromatin organization (GO:0006325), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (6): chromatin binding (GO:0003682), transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), signaling receptor binding (GO:0005102), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (11): kinetochore (GO:0000776), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear matrix (GO:0016363), SWI/SNF complex (GO:0016514), RSC-type complex (GO:0016586), brahma complex (GO:0035060), npBAF complex (GO:0071564), nBAF complex (GO:0071565), GBAF complex (GO:0140288)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
SWI/SNF chromatin remodelers	5
Gene expression (Transcription)	2
Chromatin modifying enzymes	1
Transcriptional regulation by RUNX1	1
MITF-M-dependent gene expression	1
Regulation of endogenous retroelements	1
RNA Polymerase II Transcription	1
Chromatin organization	1
Generic Transcription Pathway	1
Developmental Biology	1
Epigenetic regulation of gene expression	1
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
SWI/SNF superfamily-type complex	6
binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
positive regulation of cellular process	2
regulation of mitotic cell cycle phase transition	2
cell differentiation	2
regulation of cell differentiation	2
positive regulation of developmental process	2
nuclear lumen	2
protein-DNA complex disassembly	1
nucleosome organization	1
chromatin organization	1
transcription by RNA polymerase II	1
system development	1
cell population proliferation	1
regulation of cell population proliferation	1
metaphase/anaphase transition of mitotic cell cycle	1
regulation of metaphase/anaphase transition of cell cycle	1
T cell differentiation	1
regulation of T cell differentiation	1
positive regulation of lymphocyte differentiation	1
positive regulation of T cell activation	1
negative regulation of cellular process	1
negative regulation of developmental process	1
myoblast differentiation	1
positive regulation of cell differentiation	1
regulation of myoblast differentiation	1
transcription initiation at RNA polymerase II promoter	1
positive regulation of gene expression, epigenetic	1
regulation of cell cycle process	1
G0 to G1 transition	1
response to fatty acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
stem cell population maintenance	1
positive regulation of multicellular organismal process	1
regulation of stem cell population maintenance	1
G1/S transition of mitotic cell cycle	1
regulation of cell cycle G1/S phase transition	1

Protein interactions and networks

STRING

1982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMARCD1	SMARCC1	Q92922	999
SMARCD1	SMARCC2	Q8TAQ2	999
SMARCD1	SMARCA4	P51532	998
SMARCD1	SMARCE1	Q969G3	996
SMARCD1	SMARCB1	Q12824	995
SMARCD1	ARID1A	O14497	994
SMARCD1	ACTL6A	O96019	991
SMARCD1	DPF2	Q92785	973
SMARCD1	SMARCA2	P51531	945
SMARCD1	PPARGC1A	Q9UBK2	901
SMARCD1	TP53	P04637	842
SMARCD1	PBRM1	Q86U86	835
SMARCD1	BRD9	Q9H8M2	828
SMARCD1	PHF10	Q8WUB8	822
SMARCD1	ARID2	Q68CP9	812
SMARCD1	BANF1	O75531	812

IntAct

613 interactions, top by confidence:

A	B	Type	Score
SMARCD1	SMARCC1	psi-mi:“MI:0915”(physical association)	0.910
SMARCD1	SMARCA4	psi-mi:“MI:0915”(physical association)	0.900
SMARCA4	SMARCD1	psi-mi:“MI:0915”(physical association)	0.900
SMARCD1	SMARCA4	psi-mi:“MI:0914”(association)	0.900
SMARCB1	ARID1A	psi-mi:“MI:0914”(association)	0.860
SMARCE1	SMARCA4	psi-mi:“MI:0914”(association)	0.840
SMARCD1	SMARCC2	psi-mi:“MI:0915”(physical association)	0.800
SMARCC1	ARID1A	psi-mi:“MI:0914”(association)	0.790
VPS37B	SMARCD1	psi-mi:“MI:0915”(physical association)	0.780
SMARCD1	VPS37B	psi-mi:“MI:0915”(physical association)	0.780
SMARCD1	LDOC1	psi-mi:“MI:0915”(physical association)	0.740
SMARCD1	MED4	psi-mi:“MI:0915”(physical association)	0.720
MED4	SMARCD1	psi-mi:“MI:0915”(physical association)	0.720
SMARCD1	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.670
EP400	SMARCD1	psi-mi:“MI:0915”(physical association)	0.560
SMARCD1	ADAT2	psi-mi:“MI:0915”(physical association)	0.560
SMARCD1		psi-mi:“MI:0915”(physical association)	0.560
SMARCD1	PLAGL2	psi-mi:“MI:0915”(physical association)	0.560
CHD7	PARP1	psi-mi:“MI:0914”(association)	0.530
DPF3	SMARCA2	psi-mi:“MI:0914”(association)	0.530
SMARCD1	Nr3c1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (613): MED4 (Two-hybrid), VPS37B (Two-hybrid), SMARCD1 (Biochemical Activity), SMARCD1 (Affinity Capture-MS), SMARCD1 (Affinity Capture-MS), SMARCD1 (Affinity Capture-MS), SMARCD1 (Affinity Capture-MS), SMARCD1 (Affinity Capture-MS), SMARCD1 (Two-hybrid), CCDC85B (Two-hybrid), ARID1B (Affinity Capture-MS), ARID1A (Affinity Capture-MS), PHF10 (Affinity Capture-MS), SMARCC2 (Affinity Capture-MS), SMARCC1 (Affinity Capture-MS)

ESM2 similar proteins: A1C6X5, A1CP31, A1CTE6, A1D1Y5, A1DHK2, A2QAQ3, A2QBZ0, A2QVV2, A3LQL9, A5DCP8, B0Y7H6, B8N4F5, G0S024, G0S0Y3, G0S7B6, G0S8F1, G0SAK8, P0CP50, P0CP51, P34653, P38093, P87253, Q0CKB1, Q0CUP6, Q0CYG9, Q0D0A1, Q0UPL5, Q0V0I4, Q1E2S2, Q2GSV2, Q2H401, Q2KFH6, Q2U0M4, Q2UF60, Q2ULU6, Q2UM42, Q4IBR4, Q4P2B6, Q4WN25, Q4X0M4

Diamond homologs: E1BJD1, O02101, O54772, Q09646, Q2TBN1, Q556Z0, Q61466, Q6P9Z1, Q6STE5, Q92925, Q96GM5, Q99JR8, Q9FMT4, Q9P7S3, Q9VYG2, O74503, Q05024, Q08747, Q9SIV5

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
SMARCD1	“form complex”	“SWI/SNF complex”	binding
SMARCD1	“form complex”	GBAF	binding
SMARCD1	“form complex”	“SWI/SNF ACTL6A-ARID1A-SMARCA2 variant”	binding
SMARCD1	“form complex”	“SWI/SNF ACTL6B varian”	binding
SMARCD1	“form complex”	“Neural progenitor-specific SWI/SNF”	binding
SMARCD1	“form complex”	“Muscle cell-specific SWI/SNF ARID1A variant”	binding
SMARCD1	“form complex”	“Muscle cell-specific SWI/SNF ARID1B variant”	binding
SMARCD1	“form complex”	“Muscle cell-specific SWI/SNF SMARCA4 variant”	binding
SMARCD1	“form complex”	“Embryonic stem cell-specific SWI/SNF”	binding
CHFR	“down-regulates quantity by destabilization”	SMARCD1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 134 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
Formation of the canonical BAF (cBAF) complex	7	66.3×	6e-10
Formation of the polybromo-BAF (pBAF) complex	7	66.3×	6e-10
Formation of the embryonic stem cell BAF (esBAF) complex	7	62.8×	6e-10
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	9	61.4×	4e-12
Formation of the non-canonical BAF (ncBAF) complex	5	50.1×	1e-06
Regulation of endogenous retroelements	8	44.0×	6e-10
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	8	35.9×	3e-09
Regulation of MITF-M-dependent genes involved in pigmentation	9	35.7×	5e-10

GO biological processes:

GO term	Partners	Fold	FDR
regulation of G0 to G1 transition	9	51.4×	4e-11
nucleosome disassembly	7	47.6×	8e-09
regulation of nucleotide-excision repair	9	45.9×	6e-11
regulation of mitotic metaphase/anaphase transition	9	37.8×	3e-10
positive regulation of T cell differentiation	8	30.9×	1e-08
positive regulation of myoblast differentiation	9	27.9×	4e-09
positive regulation of double-strand break repair	9	26.2×	7e-09
regulation of G1/S transition of mitotic cell cycle	9	23.4×	1e-08

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — BRCA, MT.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	2
Uncertain significance	72
Likely benign	9
Benign	9

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1251964	NM_003076.5(SMARCD1):c.1432dup (p.Arg478fs)	Pathogenic
3897240	NM_003076.5(SMARCD1):c.592G>A (p.Glu198Lys)	Pathogenic
812679	NM_003076.5(SMARCD1):c.990C>G (p.Asp330Glu)	Pathogenic
812680	NM_003076.5(SMARCD1):c.1336A>G (p.Arg446Gly)	Pathogenic
812681	NM_003076.5(SMARCD1):c.1457G>A (p.Trp486Ter)	Pathogenic
812682	NM_003076.5(SMARCD1):c.1483T>C (p.Phe495Leu)	Pathogenic
812683	NM_003076.5(SMARCD1):c.1507C>T (p.Arg503Ter)	Pathogenic
1687715	NM_003076.5(SMARCD1):c.1051C>T (p.Arg351Cys)	Likely pathogenic
3765749	NM_003076.5(SMARCD1):c.1271T>C (p.Ile424Thr)	Likely pathogenic

SpliceAI

1820 predictions. Top by Δscore:

Variant	Effect	Δscore
12:50085544:CCGGT:C	donor_loss	1.0000
12:50085545:CGGTG:C	donor_loss	1.0000
12:50085547:G:GG	donor_gain	1.0000
12:50086349:G:GG	donor_gain	1.0000
12:50086619:A:AG	acceptor_gain	1.0000
12:50086620:G:GG	acceptor_gain	1.0000
12:50086662:GG:G	donor_gain	1.0000
12:50086663:GG:G	donor_gain	1.0000
12:50086753:A:AG	acceptor_gain	1.0000
12:50086754:A:AG	acceptor_gain	1.0000
12:50086755:G:GG	acceptor_gain	1.0000
12:50086755:GATTC:G	acceptor_gain	1.0000
12:50086874:TCAAG:T	donor_loss	1.0000
12:50086875:CAAG:C	donor_loss	1.0000
12:50086876:AAG:A	donor_loss	1.0000
12:50086880:T:G	donor_loss	1.0000
12:50086889:A:T	donor_gain	1.0000
12:50087482:GGAT:G	donor_gain	1.0000
12:50087483:GATG:G	donor_gain	1.0000
12:50088519:A:AG	acceptor_gain	1.0000
12:50088520:G:GC	acceptor_gain	1.0000
12:50088520:GT:G	acceptor_gain	1.0000
12:50088520:GTC:G	acceptor_gain	1.0000
12:50088520:GTCA:G	acceptor_gain	1.0000
12:50088633:TAGAA:T	donor_gain	1.0000
12:50088635:GAA:G	donor_gain	1.0000
12:50088636:AA:A	donor_gain	1.0000
12:50088636:AAGTG:A	donor_loss	1.0000
12:50088637:AG:A	donor_loss	1.0000
12:50088638:G:A	donor_loss	1.0000

AlphaMissense

3359 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:50086653:T:A	L133Q	1.000
12:50086766:T:C	L140P	1.000
12:50086777:T:C	S144P	1.000
12:50086778:C:T	S144F	1.000
12:50086786:T:A	Y147N	1.000
12:50086786:T:C	Y147H	1.000
12:50086786:T:G	Y147D	1.000
12:50086796:T:A	L150H	1.000
12:50086796:T:C	L150P	1.000
12:50086796:T:G	L150R	1.000
12:50086804:T:C	F153L	1.000
12:50086806:T:A	F153L	1.000
12:50086806:T:G	F153L	1.000
12:50086807:G:A	E154K	1.000
12:50086808:A:C	E154A	1.000
12:50086808:A:T	E154V	1.000
12:50086809:A:C	E154D	1.000
12:50086809:A:T	E154D	1.000
12:50086817:T:A	L157Q	1.000
12:50086817:T:C	L157P	1.000
12:50086817:T:G	L157R	1.000
12:50086819:G:C	D158H	1.000
12:50086819:G:T	D158Y	1.000
12:50086820:A:C	D158A	1.000
12:50086820:A:G	D158G	1.000
12:50086820:A:T	D158V	1.000
12:50086821:C:A	D158E	1.000
12:50086821:C:G	D158E	1.000
12:50086829:T:A	I161N	1.000
12:50086829:T:G	I161S	1.000

dbSNP variants (sampled 300 via entrez): RS1000005017 (12:50092168 T>C), RS1000062871 (12:50098221 A>G), RS1000071579 (12:50091057 G>A,C), RS1000349845 (12:50092711 G>T), RS1000409266 (12:50094891 G>A), RS1000792968 (12:50096584 A>G), RS1000846949 (12:50097926 T>C), RS1001478211 (12:50087644 T>C), RS1001514289 (12:50087101 A>G), RS1001706542 (12:50100090 G>A,T), RS1001846210 (12:50088733 T>C), RS1002137101 (12:50093805 C>A,T), RS1002359631 (12:50095261 A>G), RS1002551093 (12:50094829 G>A), RS1002671183 (12:50083499 A>C)

Disease associations

OMIM: gene MIM:601735 | disease phenotypes: MIM:618779, MIM:109200

GenCC curated gene-disease

Disease	Classification	Inheritance
Coffin-Siris syndrome 11	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant
Coffin-Siris syndrome	Supportive	Autosomal dominant

Mondo (4): Coffin-Siris syndrome 11 (MONDO:0032912), alopecia, androgenetic, 1 (MONDO:0007184), neurodevelopmental disorder (MONDO:0700092), Coffin-Siris syndrome (MONDO:0015452)

Orphanet (0):

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000085	Horseshoe kidney
HP:0000119	Abnormality of the genitourinary system
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000185	Cleft soft palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000289	Broad philtrum
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000341	Narrow forehead
HP:0000365	Hearing impairment
HP:0000414	Bulbous nose
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000574	Thick eyebrow
HP:0000684	Delayed eruption of teeth
HP:0000708	Atypical behavior
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007293_76	Body fat distribution (arm fat ratio)	4.000000e-07
GCST007294_123	Body fat distribution (trunk fat ratio)	2.000000e-09
GCST007294_2	Body fat distribution (trunk fat ratio)	1.000000e-18
GCST007295_152	Body fat distribution (leg fat ratio)	4.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C536436	Coffin-Siris syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725090 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.35	Kd	45	nM	MOLIBRESIB
6.96	IC50	110	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 7 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179151: Binding affinity against SMARCD1 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0450	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
deoxynivalenol	increases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
beta-methylcholine	affects expression	1
ICG 001	decreases expression	1
Carmustine	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lead	affects expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	decreases expression	1
Vanadium	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cadmium Chloride	increases expression	1
Coal Ash	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697213	Binding	Inhibition of SMARCD1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3HR	Abcam HEK293T SMARCD1 KO	Transformed cell line	Female
CVCL_TP58	HAP1 SMARCD1 (-) 1	Cancer cell line	Male
CVCL_TP59	HAP1 SMARCD1 (-) 2	Cancer cell line	Male
CVCL_TP60	HAP1 SMARCD1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice