SMARCAL1

Summary

SMARCAL1 (SNF2 related chromatin remodeling annealing helicase 1, HGNC:11102) is a protein-coding gene on chromosome 2q35, encoding SNF2 related chromatin remodeling annealing helicase 1 (Q9NZC9). ATP-dependent annealing helicase that binds selectively to fork DNA relative to ssDNA or dsDNA and catalyzes the rewinding of the stably unwound DNA.

The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein shows sequence similarity to the E. coli RNA polymerase-binding protein HepA. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency.

Source: NCBI Gene 50485 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Schimke immuno-osseous dysplasia (Definitive, ClinGen)
• GWAS associations: 12
• Clinical variants (ClinVar): 1,372 total — 95 pathogenic, 56 likely-pathogenic
• Phenotypes (HPO): 106
• MANE Select transcript: NM_014140

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11102
Approved symbol	SMARCAL1
Name	SNF2 related chromatin remodeling annealing helicase 1
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	HHARP, HARP
Ensembl gene	ENSG00000138375
Ensembl biotype	protein_coding
OMIM	606622
Entrez	50485

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 25 protein_coding, 9 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000357276, ENST00000358207, ENST00000392128, ENST00000412913, ENST00000425815, ENST00000427645, ENST00000430374, ENST00000434435, ENST00000444508, ENST00000445153, ENST00000479008, ENST00000486983, ENST00000496037, ENST00000697898, ENST00000697899, ENST00000697900, ENST00000697901, ENST00000697902, ENST00000697903, ENST00000697904, ENST00000697905, ENST00000697906, ENST00000697907, ENST00000697908, ENST00000697909, ENST00000697910, ENST00000697911, ENST00000860355, ENST00000860356, ENST00000860357, ENST00000860358, ENST00000860359, ENST00000932384, ENST00000932385, ENST00000932386, ENST00000932387, ENST00000932388, ENST00000956024, ENST00000956025, ENST00000956026

RefSeq mRNA: 2 — MANE Select: NM_014140 NM_001127207, NM_014140

CCDS: CCDS2403

Canonical transcript exons

ENST00000357276 — 18 exons

Exon	Start	End
ENSE00001387565	216482738	216483053
ENSE00001631368	216414647	216415515
ENSE00003972060	216475269	216475451
ENSE00003972067	216447018	216447158
ENSE00003972068	216423633	216423683
ENSE00003972076	216412484	216412648
ENSE00003972085	216450846	216451064
ENSE00003972089	216432718	216432868
ENSE00003972090	216413856	216413892
ENSE00003972091	216416257	216416307
ENSE00003972092	216477109	216477209
ENSE00003972098	216428596	216428782
ENSE00003972099	216420299	216420532
ENSE00003972100	216467944	216468046
ENSE00003972102	216464597	216464667
ENSE00003972105	216438420	216438485
ENSE00003972107	216478203	216478299
ENSE00003972108	216435338	216435496

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 85.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.5605 / max 74.8246, expressed in 1798 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25211	9.5031	1785
25213	2.2483	1352
25212	0.7935	498
202568	0.0157	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.67	gold quality
stromal cell of endometrium	CL:0002255	85.61	gold quality
sural nerve	UBERON:0015488	85.18	gold quality
ventricular zone	UBERON:0003053	84.86	gold quality
granulocyte	CL:0000094	84.84	gold quality
ganglionic eminence	UBERON:0004023	84.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.52	gold quality
adrenal tissue	UBERON:0018303	83.82	gold quality
right adrenal gland cortex	UBERON:0035827	82.84	gold quality
apex of heart	UBERON:0002098	82.72	gold quality
right adrenal gland	UBERON:0001233	82.59	gold quality
islet of Langerhans	UBERON:0000006	82.54	gold quality
cortical plate	UBERON:0005343	82.30	gold quality
monocyte	CL:0000576	82.20	gold quality
leukocyte	CL:0000738	82.14	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.08	gold quality
mononuclear cell	CL:0000842	81.86	gold quality
left adrenal gland	UBERON:0001234	81.65	gold quality
adrenal gland	UBERON:0002369	81.61	gold quality
lymph node	UBERON:0000029	81.60	gold quality
left ovary	UBERON:0002119	81.51	gold quality
gall bladder	UBERON:0002110	81.35	gold quality
ovary	UBERON:0000992	81.34	gold quality
left adrenal gland cortex	UBERON:0035825	81.28	gold quality
right ovary	UBERON:0002118	81.21	gold quality
right coronary artery	UBERON:0001625	81.19	gold quality
adrenal cortex	UBERON:0001235	81.17	gold quality
popliteal artery	UBERON:0002250	80.91	gold quality
secondary oocyte	CL:0000655	80.89	gold quality
tibial artery	UBERON:0007610	80.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.12

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• Schimke immuno-osseous dysplasia: a patient who has survived to 20 years despite having a homozygous SMARCAL1 nonsense mutation and severe early onset disease (PMID:12471207)
• Missense mutation in the SMARCAL1 gene is associated with mild Schimke immuno-osseous dysplasia. (PMID:16237566)
• Mutated in Schimke immuno-osseous dysplasia, a fatal autosomal recessive disorder. (PMID:16840568)
• Schimke immuno-osseous dysplasia (SIOD) severity within the same family might be modified by the splicing machinery. The renal expression pattern of SMARCAL1 explains a broader spectrum of renal disease in SIOD than previously described. (PMID:18356746)
• SMARCAL1 deficiency may influence brain development and function in addition to its previously recognized effect on cerebral circulation. (PMID:18520775)
• SMARCAL1 binds chromatin in vivo and that Schimke immuno-osseous dysplasia arises from impairment of diverse SMARCAL1 functions (PMID:18805831)
• study found that HARP is an ATP-dependent annealing helicase that rewinds single-stranded DNA bubbles that are stably bound by replication protein A (PMID:18974355)
• SMARCAL1 mutations: a cause of prepubertal idiopathic steroid-resistant nephrotic syndrome. (Case Report). (PMID:19127206)
• Donor serum SMARCAL1 may serve as a specific, sensitive, and noninvasive predictive marker in the assessment of cardiac graft quality. (PMID:19752368)
• SMARCAL1 directly interacts with Replication protein A (RPA) and is recruited to sites of DNA damage in an RPA-dependent manner (PMID:19793862)
• the interaction of HARP with RPA increases the concentration of annealing helicase activity in the vicinity of ssDNA regions to facilitate processes such as DNA repair (PMID:19793863)
• ARP is recruited to stalled replication forks via its direct interaction with Replication protein A (RPA) (PMID:19793864)
• SMARCAL1 is a novel DNA damage-binding protein involved in replication fork stabilization. (PMID:19841479)
• Novel compound mutations of SMARCAL1 associated with severe Schimke immuno-osseous dysplasia in a Chinese patient. (PMID:20179009)
• loss of SMARCAL1 function in patients may cause DNA replication-associated genome instability that contributes to the pleiotropic phenotypes of Schimke immuno-osseous dysplasia (PMID:21327070)
• HARP domain endows HARP with this ATP-driven annealing helicase activity. (PMID:21525954)
• SMARCAL1 continuously surveys replication forks for damage (PMID:22279047)
• SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD. (PMID:22378147)
• Review of advances in understanding of the biochemical and cellular functions of SMARCAL1 made over the recent years and discussion of the rationale for development of SMARCAL1 inhibitors as novel anticancer therapies. [Review] (PMID:22995303)
• Schimke Immunoosseous Dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child. (PMID:23630135)
• Data suggest that replication protein A (RPA) brings a complex of SMARCAL1 and WRN to stalled forks, but that they may act in different pathways to promote fork repair and restart. (PMID:23671665)
• ATR phosphorylates SMARCAL1 on S652, thereby limiting its fork regression activities and preventing aberrant fork processing (PMID:23873943)
• We present here the first evidence of intrinsic chromosomal instability in a severe SMARCAL1-deficient patient with a clinical picture of SIOD. (PMID:24197801)
• In addition to its annealing helicase activity, which eliminates the natural binding substrate for RPA, HARP blocks the phosphorylation of RPA by DNA-PK. (PMID:24565939)
• report provided the clinical and genetic description of a mild phenotype of Schimke immuno-osseous dysplasia associated with nephrotic proteinuria, decreasing after combined therapy with ACE inhibitors and sartans. (PMID:24589093)
• study reports the characterization of the RPA32C-SMARCAL1 interface at the molecular level; implications of results are discussed with respect to the recruitment of SMARCAL1 and other DNA damage response and repair proteins to stalled replication forks (PMID:24730652)
• Conserved motifs are required for RPA32 binding the the N-terminus of SMARCAL1. (PMID:24910198)
• the role of SMARCAL1 in the pathogenesis of Schimke immuno-osseous dysplasia (PMID:25319549)
• The results suggest that Smarcal1 enhances nonhomologous end-joining repair, presumably by interacting with RPA at unwound single-strand sequences and then facilitating annealing at double-strand-break ends. (PMID:26089390)
• Mutations in human SMARCAL1 that result in loss in ATPase activity lead to increased replication stress and therefore possibly manifestation of Schimke immuno-osseous dysplasia. (PMID:26195148)
• results provide the first identification, to our knowledge, of an endogenous source of replication stress that requires SMARCAL1 for resolution and define differences between members of this class of replication fork-repair enzymes. (PMID:26578802)
• SMARCAL1 negatively regulates c-myc transcription by altering the conformation of its promoter region during differentiation. (PMID:26648259)
• the replication stress response protein SMARCAL1 is a critical regulator of alternative lengthening of telomeres activity. (PMID:26832416)
• Results provide evidence that BRG1 and SMARCAL1 regulate each other. BRG1 binds to the SMARCAL1 promoter, while SMARCAL1 binds to the brg1 promoter. During DNA damage, the occupancy of SMARCAL1 on the brg1 promoter increases coinciding with an increase in BRG1 occupancy on the SMARCAL1 promoter, leading to increased brg1 and SMARCAL1 transcripts respectively. (PMID:26843359)
• the mechanism of SMARCAL1 function in maintaining genome stability (PMID:27355316)
• our data reveal the critical function of the DNA replication stress response and, specifically, Smarcal1 in hematopoietic cell survival and tumor development. Our results also provide important insight into the immunodeficiency observed in individuals with mutations in SMARCAL1 by suggesting that it is an HSPC defect. (PMID:27797382)
• deficiency of a SMARCAL1 ortholog altering the chromatin structure of a gene (PMID:27813696)
• The main roles of SMARCAL1 in DNA repair, telomere maintenance and replication fork stability in response to DNA replication stress are reviewed. (PMID:28623093)
• BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks. (PMID:28716689)
• A large number of SNF2 family, DNA and ATP-dependent motor proteins are needed during transcription, DNA replication, and DNA repair to manipulate protein-DNA interactions and change DNA structure. SMARCAL1, ZRANB3, and HLTF are three related members of this family with specialized functions that maintain genome stability during DNA replication. [review] (PMID:28954549)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	smarcal1	ENSDARG00000102265
mus_musculus	Smarcal1	ENSMUSG00000039354
rattus_norvegicus	Smarcal1	ENSRNOG00000016503

Paralogs (30): HLTF (ENSG00000071794), SMARCA2 (ENSG00000080503), SRCAP (ENSG00000080603), ATRX (ENSG00000085224), RAD54L (ENSG00000085999), BTAF1 (ENSG00000095564), CHD8 (ENSG00000100888), SMARCA1 (ENSG00000102038), CHD4 (ENSG00000111642), CHD5 (ENSG00000116254), TTF2 (ENSG00000116830), HELLS (ENSG00000119969), ZRANB3 (ENSG00000121988), CHD6 (ENSG00000124177), SMARCA4 (ENSG00000127616), INO80 (ENSG00000128908), CHD1L (ENSG00000131778), SHPRH (ENSG00000146414), SMARCA5 (ENSG00000153147), CHD1 (ENSG00000153922), SMARCAD1 (ENSG00000163104), RAD54L2 (ENSG00000164080), CHD3 (ENSG00000170004), CHD7 (ENSG00000171316), CHD2 (ENSG00000173575), CHD9 (ENSG00000177200), EP400 (ENSG00000183495), ERCC6L (ENSG00000186871), RAD54B (ENSG00000197275), ERCC6 (ENSG00000225830)

Protein

Protein identifiers

SNF2 related chromatin remodeling annealing helicase 1 — Q9NZC9 (reviewed: Q9NZC9)

Alternative names: HepA-related protein, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1, Sucrose nonfermenting protein 2-like 1

All UniProt accessions (12): A0A8V8TLB3, A0A8V8TLD4, A0A8V8TMS6, C9J6I8, C9J8F8, C9JHQ1, C9JP32, C9JS37, Q9NZC9, H7BYI2, H7C051, H7C1I3

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent annealing helicase that binds selectively to fork DNA relative to ssDNA or dsDNA and catalyzes the rewinding of the stably unwound DNA. Rewinds single-stranded DNA bubbles that are stably bound by replication protein A (RPA). Acts throughout the genome to reanneal stably unwound DNA, performing the opposite reaction of many enzymes, such as helicases and polymerases, that unwind DNA. May play an important role in DNA damage response by acting at stalled replication forks.

Subunit / interactions. Interacts with RPA2; the interaction is direct and mediates the recruitment by the RPA complex of SMARCAL1 to sites of DNA damage.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed, with high levels in testis.

Post-translational modifications. DNA damage-regulated phosphorylation by kinases that may include ATM, ATR and PRKDC.

Disease relevance. Schimke immuno-osseous dysplasia (SIOD) [MIM:242900] An autosomal recessive pleiotropic disorder characterized by spondyloepiphyseal dysplasia, renal dysfunction and immunodeficiency. Arteriosclerosis may also occur in some case. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SNF2/RAD54 helicase family. SMARCAL1 subfamily.

RefSeq proteins (2): NP_001120679, NP_054859* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000330	SNF2_N	Domain
IPR001650	Helicase_C-like	Domain
IPR010003	HARP_dom	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR038718	SNF2-like_sf	Homologous_superfamily
IPR049730	SNF2/RAD54-like_C	Domain

Pfam: PF00176, PF00271, PF07443

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (62 total): sequence variant 21, mutagenesis site 8, compositionally biased region 6, modified residue 6, sequence conflict 6, domain 4, region of interest 4, short sequence motif 2, initiator methionine 1, chain 1, coiled-coil region 1, binding site 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4MQV	X-RAY DIFFRACTION	1.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZC9-F1	70.51	0.34

Functional residue map

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

Ligand- & substrate-binding residues (1): 458–465

Post-translational modifications (6): 2, 112, 123, 129, 151, 198

Mutagenesis-validated functional residues (8):

Position	Phenotype
5	decreases interaction with rpa2.
9	decreases interaction with rpa2.
12–13	decreases interaction with rpa2.
16–17	decreases interaction with rpa2.
17–19	loss of interaction with rpa2 and impaired recruitment by the rpa complex to sites of dna damage.
20–21	decreases interaction with rpa2.
23–24	decreases interaction with rpa2.
27	decreases interaction with rpa2.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 342 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_CHROMOSOME_ORGANIZATION, GOBP_TELOMERE_ORGANIZATION, AACYNNNNTTCCS_UNKNOWN, CAGCTG_AP4_Q5, GOCC_NUCLEAR_REPLICATION_FORK, RYTAAWNNNTGAY_UNKNOWN, GOBP_DNA_DAMAGE_RESPONSE, GOBP_DNA_REPLICATION, GOMF_SINGLE_STRANDED_DNA_BINDING, GOCC_PROTEIN_DNA_COMPLEX, GOCC_REPLISOME, GOCC_SITE_OF_DOUBLE_STRAND_BREAK, GOBP_DNA_METABOLIC_PROCESS

GO Biological Process (6): DNA repair (GO:0006281), double-strand break repair via nonhomologous end joining (GO:0006303), regulation of transcription by RNA polymerase II (GO:0006357), DNA damage response (GO:0006974), replication fork processing (GO:0031297), t-circle formation (GO:0090656)

GO Molecular Function (8): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ATP-dependent DNA/DNA annealing activity (GO:0036310), nucleotide binding (GO:0000166), helicase activity (GO:0004386), protein binding (GO:0005515), ATP-dependent activity, acting on DNA (GO:0008094), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), site of double-strand break (GO:0035861), nuclear replication fork (GO:0043596), DNA replication factor A complex (GO:0005662)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ATP-dependent activity	3
DNA metabolic process	1
DNA damage response	1
double-strand break repair	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
cellular response to stress	1
DNA-templated DNA replication maintenance of fidelity	1
formation of extrachromosomal circular DNA	1
telomere maintenance via telomere trimming	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity, acting on DNA	1
DNA/DNA annealing activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
binding	1
ATP hydrolysis activity	1
catalytic activity, acting on DNA	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
site of DNA damage	1
nuclear chromosome	1
nucleus	1
replication fork	1
CMG complex	1
nuclear replisome	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

2753 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMARCAL1	RPA2	P15927	930
SMARCAL1	STN1	Q9H668	926
SMARCAL1	RAD51	Q06609	821
SMARCAL1	WRN	Q14191	816
SMARCAL1	RADX	Q6NSI4	759
SMARCAL1	MUS81	Q96NY9	739
SMARCAL1	DNA2	P51530	728
SMARCAL1	FANCM	Q8IYD8	716
SMARCAL1	RECQL	P46063	714
SMARCAL1	PRIMPOL	Q96LW4	713
SMARCAL1	BRCA2	P51587	707
SMARCAL1	FBH1	Q8NFZ0	707
SMARCAL1	PRKDC	P78527	682
SMARCAL1	EXO1	Q9UQ84	682
SMARCAL1	TIPIN	Q9BVW5	666

IntAct

69 interactions, top by confidence:

A	B	Type	Score
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
RPA1	RPA2	psi-mi:“MI:0914”(association)	0.960
RPA3	RPA2	psi-mi:“MI:0914”(association)	0.930
RPA2	SMARCAL1	psi-mi:“MI:0407”(direct interaction)	0.800
SMARCAL1	RPA2	psi-mi:“MI:0407”(direct interaction)	0.800
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
DCAF7	DIAPH1	psi-mi:“MI:0914”(association)	0.730
ANKRD44	ANKRD28	psi-mi:“MI:0914”(association)	0.710
AZIN2	OAZ2	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
PTGES3	AIP	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
ZNRD2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
PRIMPOL	RPA2	psi-mi:“MI:0914”(association)	0.510
NS1	CHD1	psi-mi:“MI:0914”(association)	0.500
TEAD2	DDX39A	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
DCAF7	DIAPH1	psi-mi:“MI:0914”(association)	0.350

BioGRID (77): SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-Western), SMARCAL1 (Affinity Capture-Western), SMARCAL1 (Affinity Capture-Western), SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-RNA), SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-RNA), SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-MS), SMARCAL1 (Affinity Capture-MS)

ESM2 similar proteins: A6H907, A6H909, B3P6R5, B4IJG7, B4NJW0, B4PUD1, B4QUC0, E1BB03, P35761, P62294, Q04913, Q0P4M4, Q1JPY4, Q28DH2, Q2NKX8, Q3U1T9, Q498E7, Q5FVG2, Q5FWF4, Q5HZN1, Q5PNU3, Q5TKR9, Q5U5Z8, Q5UE94, Q5ZIX8, Q5ZLE9, Q64702, Q6A037, Q6DJS0, Q6IRB8, Q6IVY4, Q6NZP1, Q6SJ94, Q6SJ95, Q6SJ96, Q6YY75, Q7Z2W4, Q7ZXG4, Q80Z32, Q8BZ21

Diamond homologs: A0A0P0WGX7, A1C9W6, A1CZE5, A2BGR3, A2R9H9, A4HVU6, A4IHD2, A4R227, A5E0W5, A6QQR4, A6ZL17, A6ZU34, A7EQA8, A7TJI3, A7Z019, B3LN76, B4F769, B5VE38, B6EU02, C0H4W3, C7GQI8, F4HW51, G5EF53, O13682, O14148, P0CO16, P0CO17, P0CO18, P0CO19, P0CQ66, P0CQ67, P34739, P36607, P38086, P46100, P51532, P53115, P75093, P94593, Q05471

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATR	“down-regulates activity”	SMARCAL1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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
G2/M DNA damage checkpoint	5	12.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1372 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	95
Likely pathogenic	56
Uncertain significance	422
Likely benign	624
Benign	48

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064696	NM_014140.4(SMARCAL1):c.1027_1034del (p.Phe343fs)	Pathogenic
1068979	NM_014140.4(SMARCAL1):c.1544_1569del (p.Gly515fs)	Pathogenic
1069037	NM_014140.4(SMARCAL1):c.1517del (p.Pro506fs)	Pathogenic
1069134	NM_014140.4(SMARCAL1):c.1263dup (p.Glu422fs)	Pathogenic
1070110	NM_014140.4(SMARCAL1):c.2424del (p.Val810fs)	Pathogenic
1073208	NM_014140.4(SMARCAL1):c.1000C>T (p.Arg334Ter)	Pathogenic
1074524	NM_014140.4(SMARCAL1):c.409C>T (p.Gln137Ter)	Pathogenic
1358943	NM_014140.4(SMARCAL1):c.2507del (p.Gly836fs)	Pathogenic
1359407	NM_014140.4(SMARCAL1):c.1399C>T (p.Gln467Ter)	Pathogenic
1360533	NM_014140.4(SMARCAL1):c.1632del (p.Val545fs)	Pathogenic
1410646	NM_014140.4(SMARCAL1):c.416T>A (p.Leu139Ter)	Pathogenic
1418313	NM_014140.4(SMARCAL1):c.1727del (p.Ile576fs)	Pathogenic
1434068	NM_014140.4(SMARCAL1):c.1426del (p.Arg476fs)	Pathogenic
1452431	NM_014140.4(SMARCAL1):c.1810dup (p.Gln604fs)	Pathogenic
1453416	NM_014140.4(SMARCAL1):c.1859G>A (p.Trp620Ter)	Pathogenic
1453865	NM_014140.4(SMARCAL1):c.1612C>T (p.Gln538Ter)	Pathogenic
1455796	NM_014140.4(SMARCAL1):c.1222C>T (p.Gln408Ter)	Pathogenic
1458113	NM_014140.4(SMARCAL1):c.1437dup (p.Pro480fs)	Pathogenic
1458384	NM_014140.4(SMARCAL1):c.1625del (p.Pro542fs)	Pathogenic
1458389	NM_014140.4(SMARCAL1):c.1921dup (p.Val641fs)	Pathogenic
1488622	NM_014140.4(SMARCAL1):c.2141+5G>A	Pathogenic
1683463	NM_014140.4(SMARCAL1):c.996del (p.Arg334fs)	Pathogenic
1915564	NM_014140.4(SMARCAL1):c.1169del (p.Pro390fs)	Pathogenic
1929303	NM_014140.4(SMARCAL1):c.2528+1G>A	Pathogenic
1930758	NM_014140.4(SMARCAL1):c.1611del (p.Lys537fs)	Pathogenic
1960970	NM_014140.4(SMARCAL1):c.2538dup (p.Gln847fs)	Pathogenic
1997648	NM_014140.4(SMARCAL1):c.1224dup (p.Leu409fs)	Pathogenic
1997731	NM_014140.4(SMARCAL1):c.1836C>A (p.Tyr612Ter)	Pathogenic
2002618	NM_014140.4(SMARCAL1):c.588dup (p.Ala197fs)	Pathogenic
2014519	NM_014140.4(SMARCAL1):c.530del (p.Pro177fs)	Pathogenic

SpliceAI

3785 predictions. Top by Δscore:

Variant	Effect	Δscore
2:216412562:G:GT	donor_gain	1.0000
2:216412715:G:GT	donor_gain	1.0000
2:216414881:G:GT	donor_gain	1.0000
2:216414893:GCCA:G	donor_gain	1.0000
2:216416306:GA:G	donor_gain	1.0000
2:216416308:G:GG	donor_gain	1.0000
2:216423680:C:CG	donor_gain	1.0000
2:216423684:G:GG	donor_gain	1.0000
2:216428594:A:AG	acceptor_gain	1.0000
2:216428595:G:GA	acceptor_gain	1.0000
2:216428778:GTCAA:G	donor_gain	1.0000
2:216428783:G:GG	donor_gain	1.0000
2:216435436:C:G	donor_gain	1.0000
2:216435467:C:G	donor_gain	1.0000
2:216435497:G:GG	donor_gain	1.0000
2:216435514:GTCTT:G	donor_gain	1.0000
2:216435515:TCTTT:T	donor_gain	1.0000
2:216435518:T:G	donor_gain	1.0000
2:216435518:T:TG	donor_gain	1.0000
2:216435522:G:GG	donor_gain	1.0000
2:216447013:TTTAG:T	acceptor_loss	1.0000
2:216447014:TTA:T	acceptor_loss	1.0000
2:216447015:TAG:T	acceptor_loss	1.0000
2:216447016:A:AC	acceptor_loss	1.0000
2:216447016:A:AG	acceptor_gain	1.0000
2:216447017:G:GG	acceptor_gain	1.0000
2:216447154:AACGG:A	donor_gain	1.0000
2:216447155:ACGG:A	donor_gain	1.0000
2:216447156:CGG:C	donor_gain	1.0000
2:216447156:CGGGT:C	donor_loss	1.0000

AlphaMissense

6255 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:216432860:T:A	W493R	0.999
2:216432860:T:C	W493R	0.999
2:216432764:G:C	G461R	0.998
2:216435434:A:C	S528R	0.998
2:216435436:C:A	S528R	0.998
2:216435436:C:G	S528R	0.998
2:216477121:G:C	A814P	0.998
2:216477131:G:C	R817P	0.998
2:216432785:G:C	A468P	0.997
2:216438424:A:T	E550V	0.997
2:216475363:C:A	A780D	0.997
2:216477122:C:A	A814D	0.997
2:216477130:C:A	R817S	0.997
2:216467997:C:A	A732E	0.996
2:216475371:T:C	S783P	0.996
2:216475381:C:A	A786D	0.996
2:216475384:C:A	A787D	0.996
2:216423650:T:A	W372R	0.995
2:216423650:T:C	W372R	0.995
2:216432753:C:A	A457D	0.995
2:216432755:G:C	D458H	0.995
2:216432756:A:T	D458V	0.995
2:216432771:G:A	G463E	0.995
2:216432852:G:C	R490P	0.995
2:216432862:G:C	W493C	0.995
2:216432862:G:T	W493C	0.995
2:216438439:A:T	K555I	0.995
2:216447046:G:A	G580D	0.995
2:216447055:C:A	A583D	0.995
2:216450935:G:C	K647N	0.995

dbSNP variants (sampled 300 via entrez): RS1000072894 (2:216412209 T>C), RS1000124823 (2:216412468 A>C), RS1000151912 (2:216419668 A>G), RS1000184624 (2:216443191 A>C), RS1000254471 (2:216418636 G>A,C,T), RS1000314411 (2:216425357 C>T), RS1000321263 (2:216444576 T>C), RS1000348347 (2:216425774 T>C), RS1000364340 (2:216472801 A>C,G), RS1000382841 (2:216480496 G>T), RS1000474438 (2:216425019 A>G), RS1000477347 (2:216480142 A>C), RS1000496577 (2:216431236 T>A), RS1000499450 (2:216442669 T>C), RS1000572371 (2:216444230 A>G)

Disease associations

OMIM: gene MIM:606622 | disease phenotypes: MIM:242900, MIM:606215

GenCC curated gene-disease

Disease	Classification	Inheritance
Schimke immuno-osseous dysplasia	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Schimke immuno-osseous dysplasia	Definitive	AR

Mondo (8): Schimke immuno-osseous dysplasia (MONDO:0009458), nephrotic syndrome (MONDO:0005377), focal segmental glomerulosclerosis (MONDO:0100313), kidney disorder (MONDO:0005240), microcephaly (MONDO:0001149), familial atrioventricular septal defect (MONDO:0020290), steroid-resistant nephrotic syndrome (MONDO:0044765), atypical hemolytic-uremic syndrome (MONDO:0016244)

Orphanet (3): Schimke immuno-osseous dysplasia (Orphanet:1830), Atrioventricular septal defect (Orphanet:98722), Atypical hemolytic uremic syndrome (Orphanet:2134)

HPO phenotypes

106 total (30 of 106 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000112	Nephropathy
HP:0000325	Triangular face
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000545	Myopia
HP:0000668	Hypodontia
HP:0000691	Microdontia
HP:0000707	Abnormality of the nervous system
HP:0000822	Hypertension
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0001003	Multiple lentigines
HP:0001034	Hypermelanotic macule
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001270	Motor delay
HP:0001297	Stroke
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST003329_11	Response to anti-TNF therapy in rheumatoid arthritis	1.000000e-06
GCST003329_8	Response to anti-TNF therapy in rheumatoid arthritis	3.000000e-06
GCST007044_9	Extremely high intelligence	3.000000e-08
GCST009367_3	HDL cholesterol levels x short total sleep time interaction (2df test)	6.000000e-10
GCST010102_3	White matter integrity (fractional anisotropy)	1.000000e-08
GCST010698_88	Subcortical volume (min-P)	1.000000e-18
GCST010699_97	Brain morphology (min-P)	5.000000e-12
GCST010700_52	Cortical thickness (MOSTest)	4.000000e-10
GCST010701_122	Cortical surface area (MOSTest)	7.000000e-11
GCST010702_157	Subcortical volume (MOSTest)	4.000000e-24
GCST010703_234	Brain morphology (MOSTest)	2.000000e-12
GCST011618_4	Cortical thickness	3.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004653	response to TNF antagonist
EFO:0004337	intelligence
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004641	white matter integrity
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
C536629	Schimke immunoosseous dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
geraniol	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Fulvestrant	decreases methylation	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Catechin	decreases expression, affects cotreatment	1
Cisplatin	affects expression	1
Ivermectin	increases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	decreases expression	1
Cyclosporine	increases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

8 cell lines: 7 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B7ZD	Abcam Raji SMARCAL1 KO	Cancer cell line	Male
CVCL_C0A6	Abcam THP-1 SMARCAL1 KO	Cancer cell line	Male
CVCL_C7BU	Abcam PC-3 SMARCAL1 KO	Cancer cell line	Male
CVCL_D0LL	SDASi001-A	Induced pluripotent stem cell	Female
CVCL_E2K7	HAP1 SMARCAL1 (-) 1	Cancer cell line	Male
CVCL_E2K8	HAP1 SMARCAL1 (-) 2	Cancer cell line	Male
CVCL_E2K9	HAP1 SMARCAL1 (-) 3	Cancer cell line	Male
CVCL_F1RE	HyCyte LN-229 KO-hSMARCAL1	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT00001212	PHASE2	COMPLETED	Drug Therapy in Lupus Nephropathy
NCT00001959	PHASE2	COMPLETED	Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
NCT00004466	PHASE2	TERMINATED	Pilot Study of Atorvastatin in Children With Chronic Hyperlipidemia Secondary to Nephrotic Syndrome
NCT00004990	PHASE2	COMPLETED	Once-A-Month Steroid Treatment for Patients With Focal Segmental Glomerulosclerosis
NCT00977977	PHASE2	RECRUITING	Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy
NCT02394106	PHASE2	TERMINATED	Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome
NCT02394119	PHASE2	COMPLETED	Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT02966717	PHASE2	UNKNOWN	Rituximab Combined With MSCs in the Treatment of PNS (3-4 Stage of CKD)
NCT03004001	PHASE2	TERMINATED	Effect of PCSK9-Antibody (Alirocumab) on Dyslipidemia Secondary to Nephrotic Syndrome
NCT03949855	PHASE2	RECRUITING	Belimumab With Rituximab for Primary Membranous Nephropathy
NCT05599815	PHASE2	WITHDRAWN	Part 1 - A Clinical Trial in Patients With Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome
NCT05704400	PHASE2	UNKNOWN	Efficacy of Anti-CD20 Ab Associated With Anti-CD38 in the Childhood Multidrug Dependent and Resistant Nephrotic Syndrome
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases