SMARCAD1

Summary

SMARCAD1 (SNF2 related chromatin remodeling ATPase with DExD box 1, HGNC:18398) is a protein-coding gene on chromosome 4q22.3, encoding SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 (Q9H4L7). Protein that possesses intrinsic ATP-dependent nucleosome-remodeling activity and is both required for DNA repair and heterochromatin organization.

This gene encodes a member of the SNF subfamily of helicase proteins. The encoded protein plays a critical role in the restoration of heterochromatin organization and propagation of epigenetic patterns following DNA replication by mediating histone H3/H4 deacetylation. Mutations in this gene are associated with adermatoglyphia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 56916 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ectodermal dysplasia syndrome (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 18
• Clinical variants (ClinVar): 158 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 34
• MANE Select transcript: NM_020159

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18398
Approved symbol	SMARCAD1
Name	SNF2 related chromatin remodeling ATPase with DExD box 1
Location	4q22.3
Locus type	gene with protein product
Status	Approved
Aliases	ETL1, DKFZP762K2015, KIAA1122, DKFZp762K2015
Ensembl gene	ENSG00000163104
Ensembl biotype	protein_coding
OMIM	612761
Entrez	56916

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000354268, ENST00000359052, ENST00000394961, ENST00000457823, ENST00000506089, ENST00000509418, ENST00000510105, ENST00000514232, ENST00000902279, ENST00000902280, ENST00000902281, ENST00000929855, ENST00000929856, ENST00000971285

RefSeq mRNA: 9 — MANE Select: NM_020159 NM_001128429, NM_001128430, NM_001254949, NM_001375855, NM_001375856, NM_001375857, NM_001375858, NM_001375859, NM_020159

CCDS: CCDS3639, CCDS47101, CCDS58914

Canonical transcript exons

ENST00000354268 — 24 exons

Exon	Start	End
ENSE00001071632	94208346	94208584
ENSE00001071643	94278929	94279050
ENSE00001835090	94289473	94291292
ENSE00001840343	94207865	94208070
ENSE00003477568	94233954	94234122
ENSE00003481937	94250752	94250833
ENSE00003485495	94278422	94278517
ENSE00003497052	94280592	94280780
ENSE00003516912	94274890	94274965
ENSE00003517760	94278616	94278733
ENSE00003521410	94270728	94270818
ENSE00003530882	94274738	94274797
ENSE00003534856	94281472	94281590
ENSE00003572031	94276339	94276474
ENSE00003573353	94277022	94277159
ENSE00003574807	94284960	94285069
ENSE00003576828	94283121	94283303
ENSE00003592700	94273617	94273716
ENSE00003601264	94249654	94249755
ENSE00003605632	94252616	94253007
ENSE00003614533	94226119	94226296
ENSE00003644028	94240906	94241006
ENSE00003658077	94264707	94264906
ENSE00003658345	94236952	94237018

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 93.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.7599 / max 377.3761, expressed in 1803 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48908	14.3889	1764
48910	11.4608	1761
48911	3.2521	1417
48909	1.6183	882
48913	0.0397	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	93.44	gold quality
ganglionic eminence	UBERON:0004023	93.23	gold quality
tibia	UBERON:0000979	93.16	gold quality
cortical plate	UBERON:0005343	92.57	gold quality
secondary oocyte	CL:0000655	91.41	gold quality
epithelial cell of pancreas	CL:0000083	91.14	silver quality
ventricular zone	UBERON:0003053	90.74	gold quality
calcaneal tendon	UBERON:0003701	90.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.32	gold quality
upper leg skin	UBERON:0004262	90.16	gold quality
visceral pleura	UBERON:0002401	89.70	gold quality
parietal pleura	UBERON:0002400	89.62	gold quality
right uterine tube	UBERON:0001302	89.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.49	gold quality
oocyte	CL:0000023	88.46	gold quality
upper arm skin	UBERON:0004263	87.77	gold quality
germinal epithelium of ovary	UBERON:0001304	87.71	gold quality
endometrium	UBERON:0001295	87.02	gold quality
left ovary	UBERON:0002119	86.87	gold quality
ileal mucosa	UBERON:0000331	86.80	gold quality
pancreatic ductal cell	CL:0002079	86.76	silver quality
smooth muscle tissue	UBERON:0001135	86.71	gold quality
right ovary	UBERON:0002118	86.61	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.51	gold quality
metanephros	UBERON:0000081	86.47	gold quality
ovary	UBERON:0000992	86.28	gold quality
rectum	UBERON:0001052	86.28	gold quality
cerebellar hemisphere	UBERON:0002245	86.26	gold quality
cerebellar cortex	UBERON:0002129	86.25	gold quality
corpus epididymis	UBERON:0004359	86.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.10

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

183 targeting SMARCAD1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6758-5P	100.00	66.21	1470
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-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4803	99.98	71.99	3117
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790

Literature-anchored findings (GeneRIF, showing 18)

• Results suggest a novel model for gene regulation via the SMARCAD1/KIAA1122 protein complex. (PMID:18675275)
• Findings suggest that chromatin remodeling by SMARCAD1 ensures that silenced loci, such as pericentric heterochromatin, are correctly perpetuated. (PMID:21549307)
• The existence of a short isoform of SMARCAD1 exclusively expressed in the skin, is demonstrated. (PMID:21820097)
• findings unveil an evolutionarily conserved role for the Fun30 and SMARCAD1 chromatin remodellers in controlling end resection, homologous recombination and genome stability in the context of chromatin (PMID:22960744)
• These data indicate a pivotal role for the SMARCAD1-skin specific isoform in dermatoglyph formation, ADG and epidermal differientation gene expression (PMID:24909267)
• A splice variant (c.378+1G>T) in the SMARCAD1 gene co-segregated with Basan syndrome in a large Chinese family. (PMID:26932190)
• These results indicate that SMARCAD1 is involved in breast cancer metastasis (PMID:27232533)
• BRCA1-BARD1 ligase activity and subsequent SMARCAD1-dependent chromatin remodeling are critical regulators of DNA repair in cancer cells. (PMID:27239795)
• Data suggest that retention of SMARCAD1 in nucleus is dependent on interaction of CUE1 domain of SMARCAD1 with RBCC domain of KAP1; these studies were conducted with recombinant proteins expressed in mouse embryonic stem cell line and human somatic cell line. (SMARCAD1 = ATP-dependent helicase-1; KAP1 = KRAB-interacting protein-1) (PMID:29284678)
• Whole-genome sequencing on DNA from affected individuals with Huriez syndrome from three families revealed three not previously reported SNPs in SMARCAD1 gene. Western blot experiments confirmed the reduced expression of Smarcad1 protein in keratinocytes and fibroblasts from patients compared with healthy controls. Study concluded that haploinsufficiency for the skin-specific SMARCAD1 isoform accounts for Huriez syndrome. (PMID:29409814)
• identifies Smarcad1/Fun30 as an accessory factor for the mismatch repair reaction (PMID:29899141)
• SMARCAD1 knockdown resulted in a significant decrease in breast cancer cell proliferation and colony formation, leading to the significant inhibition of tumour growth in both the chick embryo and nude mouse xenograft models. This inhibition was due, at least in part, to a decrease in IKKbeta expression. (PMID:30308496)
• A structural model of the KAP1 RBCC domain-SMARCAD1 CUE1 domain complex is presented. SMARCAD1 CUE1 has higher affinity for KAP1 RBCC than monoubiquitin. CUE1 binds an exposed coiled-coil surface on KAP1, not a domain resembling ubiquitin. (PMID:31204252)
• SMARCAD1-mediated recruitment of the DNA mismatch repair protein MutLalpha to MutSalpha on damaged chromatin induces apoptosis in human cells. (PMID:31843968)
• Huriez syndrome caused by a large deletion that abrogates the skin-specific isoform of SMARCAD1. (PMID:33400266)
• MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1. (PMID:37140056)
• The Conserved Chromatin Remodeler SMARCAD1 Interacts with TFIIIC and Architectural Proteins in Human and Mouse. (PMID:37761933)
• Basan syndrome in a family from South India: a novel SMARCAD1 variant. (PMID:37966719)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	smarcad1a	ENSDARG00000014041
danio_rerio	smarcad1b	ENSDARG00000073721
mus_musculus	Smarcad1	ENSMUSG00000029920
rattus_norvegicus	Smarcad1	ENSRNOG00000006391
drosophila_melanogaster	Etl1	FBGN0032157
caenorhabditis_elegans		WBGENE00010845

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), SMARCAL1 (ENSG00000138375), SHPRH (ENSG00000146414), SMARCA5 (ENSG00000153147), CHD1 (ENSG00000153922), RAD54L2 (ENSG00000164080), CHD3 (ENSG00000170004), CHD7 (ENSG00000171316), CHD2 (ENSG00000173575), CHD9 (ENSG00000177200), EP400 (ENSG00000183495), ERCC6L (ENSG00000186871), RAD54B (ENSG00000197275), ERCC6 (ENSG00000225830)

Protein

Protein identifiers

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1 — Q9H4L7 (reviewed: Q9H4L7)

All UniProt accessions (3): D6RAY8, Q9H4L7, F8W9M2

UniProt curated annotations — full annotation on UniProt →

Function. Protein that possesses intrinsic ATP-dependent nucleosome-remodeling activity and is both required for DNA repair and heterochromatin organization. Combines the ATP-dependent ability to exchange histones, with the chaperone-like ATP-independent activity to deposit histones and assemble nucleosomes. Promotes DNA end resection of double-strand breaks (DSBs) following DNA damage: probably acts by weakening histone DNA interactions in nucleosomes flanking DSBs. Required for the restoration of heterochromatin organization after replication. Acts at replication sites to facilitate the maintenance of heterochromatin by directing H3 and H4 histones deacetylation, H3 ‘Lys-9’ trimethylation (H3K9me3) and restoration of silencing.

Subunit / interactions. Binds to DNA preferentially in the vicinity of transcriptional start sites. Interacts with MSH2 and TRIM28. Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2. Interacts with PCNA.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Isoform 1 is expressed ubiquitously. Isoform 3 is expressed mainly in skin and esophagus. Expressed in fibroblasts and keratinocytes (at protein level).

Post-translational modifications. Phosphorylation at the C-terminus promotes histone binding but impedes nucleosome binding. Phosphorylation impedes ATPase activity and histone exchange activity.

Disease relevance. Adermatoglyphia (ADERM) [MIM:136000] An autosomal dominant condition characterized by the lack of epidermal ridges on the palms and soles, which results in the absence of fingerprints, and is associated with a reduced number of sweat gland openings and reduced sweating of palms and soles. The disease is caused by variants affecting the gene represented in this entry. Splice site mutations causing aberrant splicing of skin-specific isoform 3 are likely to exert a loss-of-function effect and are involved in ADERM. Basan syndrome (BSNS) [MIM:129200] An autosomal dominant form of adermatoglyphia associated with congenital facial milia, acral blistering, digital contractures, and nail abnormalities. Adermatoglyphia is defined by the lack of epidermal ridges on the palms and soles, which results in the absence of fingerprints. The disease is caused by variants affecting the gene represented in this entry. Splice site mutations causing aberrant splicing of skin-specific isoform 3 are likely to exert a loss-of-function effect and are involved in BSNS. Huriez syndrome (HRZ) [MIM:181600] An autosomal dominant syndrome characterized by atrophic fibrosis of the skin of the limbs, nail hypoplasia, and palmoplantar keratoderma. Malignant degeneration of affected skin resulting in aggressive squamous cell carcinoma and early metastasis formation is a distinctive feature of the syndrome. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Skin-specific.

Similarity. Belongs to the SNF2/RAD54 helicase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H4L7-1	1, Long	yes
Q9H4L7-2	2
Q9H4L7-3	3, Short

RefSeq proteins (9): NP_001121901, NP_001121902, NP_001241878, NP_001362784, NP_001362785, NP_001362786, NP_001362787, NP_001362788, NP_064544* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000330	SNF2_N	Domain
IPR001650	Helicase_C-like	Domain
IPR003892	CUE	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

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (66 total): modified residue 27, sequence variant 8, cross-link 6, domain 4, region of interest 4, short sequence motif 3, compositionally biased region 3, helix 3, binding site 2, splice variant 2, sequence conflict 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7Z36	X-RAY DIFFRACTION	2.8
9JAO	ELECTRON MICROSCOPY	3.1
6QU1	X-RAY DIFFRACTION	3.7
6H3A	X-RAY DIFFRACTION	5.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H4L7-F1	67.76	0.20

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 (2): 521–529; 897–904

Post-translational modifications (33): 1, 39, 54, 57, 66, 67, 71, 79, 95, 96, 124, 127, 132, 146, 152, 211, 212, 213, 214, 217 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
528	no effect on subcellular localization and on histone deacetylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 292 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_REGULATION_OF_DNA_RECOMBINATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, TATTATA_MIR374, GOBP_CHROMOSOME_SEPARATION, CAGGTCC_MIR492, GTGCCTT_MIR506, GOCC_NUCLEAR_REPLICATION_FORK, NFKB_C, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, MUELLER_PLURINET, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5, GOBP_DNA_DAMAGE_RESPONSE, ATF4_Q2

GO Biological Process (9): regulation of DNA recombination (GO:0000018), DNA double-strand break processing (GO:0000729), chromatin remodeling (GO:0006338), heterochromatin formation (GO:0031507), positive regulation of transcription by RNA polymerase II (GO:0045944), chromosome separation (GO:0051304), DNA repair (GO:0006281), chromatin organization (GO:0006325), DNA damage response (GO:0006974)

GO Molecular Function (13): DNA binding (GO:0003677), DNA helicase activity (GO:0003678), chromatin binding (GO:0003682), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ubiquitin binding (GO:0043130), ATP-dependent chromatin remodeler activity (GO:0140658), ATP-dependent histone chaperone activity (GO:0140674), nucleosome array spacer activity (GO:0140750), nucleotide binding (GO:0000166), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): chromatin (GO:0000785), heterochromatin (GO:0000792), nucleus (GO:0005634), nucleoplasm (GO:0005654), site of double-strand break (GO:0035861), nuclear replication fork (GO:0043596), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
ATP-dependent activity, acting on DNA	2
binding	2
ATP-dependent activity	2
cellular anatomical structure	2
DNA recombination	1
regulation of DNA metabolic process	1
double-strand break repair	1
5’-3’ DNA exonuclease activity	1
chromatin organization	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
chromosome segregation	1
cell cycle process	1
DNA damage response	1
cellular component organization	1
cellular response to stress	1
nucleic acid binding	1
helicase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ubiquitin-like protein binding	1
DNA binding	1
chromatin remodeling	1
catalytic activity, acting on a protein	1
ATP-dependent chromatin remodeler activity	1
histone chaperone activity	1
histone octamer slider activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
chromosome	1

Protein interactions and networks

STRING

2510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMARCAD1	TRIM28	Q13263	917
SMARCAD1	H2AC20	Q16777	762
SMARCAD1	H2AC19	P20670	761
SMARCAD1	MSH2	P43246	743
SMARCAD1	EXO1	Q9UQ84	665
SMARCAD1	DNA2	P51530	647
SMARCAD1	TOPBP1	Q92547	646
SMARCAD1	HDAC1	Q13547	575
SMARCAD1	TP53BP1	Q12888	564
SMARCAD1	BRCA1	P38398	548
SMARCAD1	EHMT2	Q96KQ7	534
SMARCAD1	TRIM17	Q9Y577	493
SMARCAD1	BARD1	Q99728	480
SMARCAD1	RBBP8	Q99708	471
SMARCAD1	RAD9A	Q99638	460

IntAct

79 interactions, top by confidence:

A	B	Type	Score
MSH2	MSH3	psi-mi:“MI:0914”(association)	0.920
CEP19	CEP43	psi-mi:“MI:0914”(association)	0.770
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
USP20	HIF1A	psi-mi:“MI:0914”(association)	0.630
ZNF223	PPM1G	psi-mi:“MI:0914”(association)	0.530
ZNF764	IPO8	psi-mi:“MI:0914”(association)	0.530
MSH6	PCNA	psi-mi:“MI:0914”(association)	0.530
TRIM28	ZNF316	psi-mi:“MI:0914”(association)	0.530
ZNF764	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
ZNF324B	ZNF316	psi-mi:“MI:0914”(association)	0.530
ZNF689	ZNF593	psi-mi:“MI:0914”(association)	0.530
ZNF562	ISLR	psi-mi:“MI:0914”(association)	0.530
ZNF816	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
ZNF214	LRP4	psi-mi:“MI:0914”(association)	0.530
TRIM28	ZNF320	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
ZNF785	TRIO	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
SUMO1	SMARCAD1	psi-mi:“MI:0407”(direct interaction)	0.440
SMARCAD1	NUMA1	psi-mi:“MI:0915”(physical association)	0.400
SMARCAD1	RPL4	psi-mi:“MI:0915”(physical association)	0.400
SMARCAD1	CFAP418	psi-mi:“MI:0915”(physical association)	0.370
EPHA2	SSR3	psi-mi:“MI:0914”(association)	0.350
FOXL1	DDX39A	psi-mi:“MI:0914”(association)	0.350
ZFP14	IPO8	psi-mi:“MI:0914”(association)	0.350

BioGRID (273): SMARCAD1 (Affinity Capture-MS), SMARCAD1 (Affinity Capture-MS), ANP32A (Co-fractionation), SMARCAD1 (Co-fractionation), SMARCAD1 (Co-fractionation), SMARCAD1 (Affinity Capture-MS), SMARCAD1 (Proximity Label-MS), SMARCAD1 (Affinity Capture-MS), SMARCAD1 (Affinity Capture-MS), SMARCAD1 (Affinity Capture-MS), SMARCAD1 (Affinity Capture-MS), SMARCAD1 (Two-hybrid), SMARCAD1 (Reconstituted Complex), SMARCAD1 (Two-hybrid), SMARCAD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0P0WGX7, A2BGR3, A3KFM7, A3KMI0, A4IHD2, A4PBL4, A6QQR4, B0R061, D3Z9Z9, D3ZA12, E1B7X9, F4I2H2, F4I9Q5, F4J9M5, F4JTF6, F4K128, F8VPZ5, G5EDG2, O14139, O18017, O42861, P0CQ66, P0CQ67, P32657, P32849, P32863, P40352, P87114, Q03468, Q04692, Q0D622, Q0PCS3, Q0WVW7, Q2NKX8, Q5FWR0, Q60EX7, Q6P158, Q6PGC1, Q7F2E4, Q7Z478

Diamond homologs: A0A0P0WGX7, A2A8L1, A2BGR3, A3KFM7, A6QQR4, A7Z019, A9X4T1, B0R0I6, B0XPE7, B3NAN8, B4GS98, B5BT18, B5DE69, B6ZLK2, D3Z9Z9, D3ZA12, D3ZD32, E1B7X9, F1Q8K0, F4I2H2, F4IV45, F4J9M5, F4JY24, F4K128, F4KBP5, F8VPZ5, G5EBZ4, G5EF53, O12944, O13682, O14139, O14646, O14981, O43065, O76460, P0CO16, P0CO17, P28370, P31380, P32333

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SMARCAD1	“up-regulates activity”	HDAC1	binding
SMARCAD1	“up-regulates activity”	TRIM28	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 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
Regulation of endogenous retroelements by KRAB-ZFP proteins	6	7.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	87
Likely benign	10
Benign	21

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
187776	NM_020159.5(SMARCAD1):c.1281+665G>A	Pathogenic
187777	NM_020159.5(SMARCAD1):c.1281+666T>C	Pathogenic
187778	NM_020159.5(SMARCAD1):c.1281+669G>C	Pathogenic
187779	NM_020159.5(SMARCAD1):c.1281+667A>T	Pathogenic
30981	NM_020159.5(SMARCAD1):c.1281+665G>T	Pathogenic
620663	NM_020159.5(SMARCAD1):c.1281+649_1281+666del	Pathogenic
620664	NM_020159.5(SMARCAD1):c.1281+666dup	Likely pathogenic

SpliceAI

3520 predictions. Top by Δscore:

Variant	Effect	Δscore
4:94208581:ACAGG:A	donor_loss	1.0000
4:94208583:AGGT:A	donor_loss	1.0000
4:94208584:GGT:G	donor_loss	1.0000
4:94208586:T:A	donor_loss	1.0000
4:94226108:T:G	acceptor_gain	1.0000
4:94226115:GCAGA:G	acceptor_loss	1.0000
4:94226117:A:AG	acceptor_gain	1.0000
4:94226117:A:C	acceptor_loss	1.0000
4:94226118:G:GG	acceptor_gain	1.0000
4:94226118:GA:G	acceptor_gain	1.0000
4:94226118:GAA:G	acceptor_gain	1.0000
4:94226118:GAAGA:G	acceptor_gain	1.0000
4:94226281:A:G	donor_gain	1.0000
4:94226295:GT:G	donor_gain	1.0000
4:94226297:G:GG	donor_gain	1.0000
4:94233945:T:G	acceptor_gain	1.0000
4:94233953:GTTCT:G	acceptor_gain	1.0000
4:94234048:G:GT	donor_gain	1.0000
4:94234084:G:GT	donor_gain	1.0000
4:94234085:A:T	donor_gain	1.0000
4:94234100:G:GT	donor_gain	1.0000
4:94234100:GAA:G	donor_gain	1.0000
4:94234103:G:GG	donor_gain	1.0000
4:94234118:T:TG	donor_gain	1.0000
4:94236941:C:A	acceptor_gain	1.0000
4:94236946:T:A	acceptor_gain	1.0000
4:94236949:TAGT:T	acceptor_loss	1.0000
4:94236950:A:AG	acceptor_gain	1.0000
4:94236950:A:T	acceptor_loss	1.0000
4:94236950:AGTT:A	acceptor_gain	1.0000

AlphaMissense

6877 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:94252928:T:C	L401P	1.000
4:94270818:G:A	M524I	1.000
4:94270818:G:C	M524I	1.000
4:94270818:G:T	M524I	1.000
4:94273617:G:C	G525R	1.000
4:94273624:G:A	G527E	1.000
4:94273624:G:T	G527V	1.000
4:94273627:A:T	K528I	1.000
4:94273699:T:A	V552D	1.000
4:94274743:T:A	W560R	1.000
4:94274743:T:C	W560R	1.000
4:94274904:C:A	R583S	1.000
4:94274905:G:C	R583P	1.000
4:94276371:G:C	R614P	1.000
4:94276412:G:C	D628H	1.000
4:94276413:A:C	D628A	1.000
4:94276413:A:T	D628V	1.000
4:94276416:A:C	E629A	1.000
4:94276416:A:T	E629V	1.000
4:94276428:T:C	L633P	1.000
4:94276461:T:C	L644P	1.000
4:94277041:T:C	L655P	1.000
4:94277046:G:C	G657R	1.000
4:94277046:G:T	G657C	1.000
4:94277047:G:A	G657D	1.000
4:94277077:T:C	L667P	1.000
4:94277094:T:C	F673L	1.000
4:94277096:T:A	F673L	1.000
4:94277096:T:G	F673L	1.000
4:94280662:T:C	L830P	1.000

dbSNP variants (sampled 300 via entrez): RS1000013299 (4:94238907 G>A), RS10000247 (4:94252099 G>A,C,T), RS1000061777 (4:94287065 C>T), RS1000097818 (4:94208256 C>T), RS1000154079 (4:94245011 C>T), RS1000178767 (4:94278109 A>G), RS1000182794 (4:94238903 C>G,T), RS1000220529 (4:94289952 T>A), RS1000233465 (4:94236289 A>G), RS1000243515 (4:94247539 A>C,G), RS1000270875 (4:94286382 A>G), RS1000300250 (4:94271701 C>A,T), RS10003038 (4:94243824 T>C), RS1000353185 (4:94227579 A>G), RS1000388398 (4:94241967 C>T)

Disease associations

OMIM: gene MIM:612761 | disease phenotypes: MIM:129200, MIM:136000, MIM:181600

GenCC curated gene-disease

Disease	Classification	Inheritance
ectodermal dysplasia syndrome	Definitive	Autosomal dominant
isolated congenital adermatoglyphia	Strong	Autosomal dominant
palmoplantar keratoderma-sclerodactyly syndrome	Moderate	Autosomal dominant
absence of fingerprints-congenital milia syndrome	Supportive	Autosomal dominant

Mondo (5): absence of fingerprints-congenital milia syndrome (MONDO:0007507), isolated congenital adermatoglyphia (MONDO:0007619), palmoplantar keratoderma-sclerodactyly syndrome (MONDO:0008416), neurodevelopmental disorder (MONDO:0700092), ectodermal dysplasia syndrome (MONDO:0019287)

Orphanet (3): Absence of fingerprints-congenital milia syndrome (Orphanet:1658), Isolated congenital adermatoglyphia (Orphanet:289465), Huriez syndrome (Orphanet:384)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000954	Single transverse palmar crease
HP:0000958	Dry skin
HP:0000963	Thin skin
HP:0000966	Hypohidrosis
HP:0000968	Ectodermal dysplasia
HP:0000982	Palmoplantar keratoderma
HP:0000988	Skin rash
HP:0001034	Hypermelanotic macule
HP:0001056	Milia
HP:0001072	Thickened skin
HP:0001182	Tapered finger
HP:0001217	Clubbing
HP:0001597	Abnormal nail morphology
HP:0001792	Small nail
HP:0003623	Neonatal onset
HP:0006739	Squamous cell carcinoma of the skin
HP:0007455	Adermatoglyphia
HP:0007477	Abnormal dermatoglyphics
HP:0007545	Congenital palmoplantar hyperkeratosis
HP:0008065	Aplasia/Hypoplasia of the skin
HP:0008066	Abnormal blistering of the skin
HP:0008404	Nail dystrophy
HP:0009775	Amniotic constriction ring
HP:0010621	Cutaneous syndactyly of toes
HP:0010765	Palmar hyperkeratosis
HP:0011838	Sclerodactyly
HP:0025092	Epidermal acanthosis
HP:0030044	Flexion contracture of digit
HP:0031045	Acral blistering

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001368_12	Capecitabine sensitivity	7.000000e-06
GCST002023_3	Testicular germ cell tumor	1.000000e-08
GCST002500_52	QT interval	1.000000e-09
GCST002541_10	Menarche (age at onset)	1.000000e-10
GCST004635_9	Testicular germ cell tumor	3.000000e-08
GCST004713_17	Testicular germ cell tumor	1.000000e-06
GCST005830_78	Hand grip strength	7.000000e-09
GCST006288_209	Heel bone mineral density	2.000000e-06
GCST006288_527	Heel bone mineral density	5.000000e-11
GCST006979_445	Heel bone mineral density	7.000000e-29
GCST007856_43	Colorectal cancer or advanced adenoma	1.000000e-08
GCST008502_4	Low susceptibility to hepatitis C infection	5.000000e-06
GCST009379_264	Type 2 diabetes	4.000000e-11
GCST010699_107	Brain morphology (min-P)	2.000000e-11
GCST010701_106	Cortical surface area (MOSTest)	3.000000e-12
GCST010702_56	Subcortical volume (MOSTest)	4.000000e-12
GCST010703_63	Brain morphology (MOSTest)	2.000000e-08
GCST010919_10	QT interval	8.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004703	age at menarche
EFO:0006941	grip strength measurement
EFO:0009270	heel bone mineral density
EFO:0010101	decreased susceptibility to hepatitis C infection
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004476	Ectodermal Dysplasia	C16.131.077.350; C16.131.831.350; C16.320.850.250; C17.800.804.350; C17.800.827.250
D065886	Neurodevelopmental Disorders	F03.625
C537659	Basan syndrome (supp.)
C565010	Fingerprints, Absence of (supp.)
C537526	Sclerotylosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11722476	SMARCAD1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
coumarin	affects phosphorylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Atrazine	decreases expression	1
Caffeine	increases phosphorylation	1
Gold	decreases expression	1
Quercetin	increases phosphorylation	1
Rotenone	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin M1	decreases expression	1

Clinical trials (associated diseases)

210 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
NCT00001211	Not specified	COMPLETED	Clinical Study of Oral Endosseous Titanium Implants in Edentulous Subjects
NCT00266513	Not specified	TERMINATED	Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States
NCT01108770	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia
NCT02896387	Not specified	TERMINATED	Ability of a Molecule (Prima) to Restore Physiological Differentiation in Epithelium Expressing Gene p63
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07468019	Not specified	RECRUITING	Organization’s Unique Protocol ID
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