SAMD1

Summary

SAMD1 (sterile alpha motif domain containing 1, HGNC:17958) is a protein-coding gene on chromosome 19p13.12, encoding Sterile alpha motif domain-containing protein 1 (Q6SPF0). Unmethylated CpG islands (CGIs)-binding protein which localizes to H3K4me3-decorated CGIs, where it acts as a transcriptional repressor.

Enables chromatin binding activity. Involved in negative regulation of transcription initiation-coupled chromatin remodeling and protein homooligomerization. Is active in nucleus.

Source: NCBI Gene 90378 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 15 total
• MANE Select transcript: NM_138352

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17958
Approved symbol	SAMD1
Name	sterile alpha motif domain containing 1
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141858
Ensembl biotype	protein_coding
OMIM	620206
Entrez	90378

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000269724, ENST00000533683, ENST00000541938

RefSeq mRNA: 1 — MANE Select: NM_138352 NM_138352

Canonical transcript exons

ENST00000533683 — 5 exons

Exon	Start	End
ENSE00000951098	14088880	14088976
ENSE00000951099	14088671	14088782
ENSE00002169502	14089785	14090751
ENSE00002254239	14087851	14088575
ENSE00003521494	14089068	14089362

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 97.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.8761 / max 310.2371, expressed in 1803 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179604	14.8024	1760
179603	9.0658	1709
179601	2.0971	1138
179605	1.9007	1169
179606	1.2927	823
179600	0.9846	579
179602	0.6593	406
208704	0.0735	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	97.69	gold quality
cortical plate	UBERON:0005343	95.51	gold quality
mucosa of transverse colon	UBERON:0004991	95.36	gold quality
ganglionic eminence	UBERON:0004023	94.34	gold quality
ventricular zone	UBERON:0003053	93.82	gold quality
lower esophagus mucosa	UBERON:0035834	93.54	gold quality
amygdala	UBERON:0001876	93.33	gold quality
temporal lobe	UBERON:0001871	93.32	gold quality
spinal cord	UBERON:0002240	92.92	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.91	gold quality
substantia nigra	UBERON:0002038	92.67	gold quality
apex of heart	UBERON:0002098	92.46	gold quality
Ammon’s horn	UBERON:0001954	92.37	gold quality
putamen	UBERON:0001874	91.96	gold quality
hypothalamus	UBERON:0001898	91.82	gold quality
gastrocnemius	UBERON:0001388	91.76	gold quality
anterior cingulate cortex	UBERON:0009835	91.65	gold quality
primary visual cortex	UBERON:0002436	91.24	gold quality
prefrontal cortex	UBERON:0000451	91.19	gold quality
right frontal lobe	UBERON:0002810	91.17	gold quality
cerebral cortex	UBERON:0000956	91.07	gold quality
frontal cortex	UBERON:0001870	91.07	gold quality
heart left ventricle	UBERON:0002084	91.04	gold quality
caudate nucleus	UBERON:0001873	91.01	gold quality
muscle of leg	UBERON:0001383	90.64	gold quality
nucleus accumbens	UBERON:0001882	90.51	gold quality
brain	UBERON:0000955	90.20	gold quality
skin of abdomen	UBERON:0001416	90.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.06	gold quality
transverse colon	UBERON:0001157	90.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.45

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 4)

• atherin is present only in atherosclerotic lesions, not in normal intima (PMID:16159594)
• The nuclear importin IPO5 was identified as a novel interacting protein of SMAD1. Overexpression of IPO5 in various cell lines specifically increases nuclear localization of BMP receptor-activated SMADs (R-SMADs) confirming a functional relationship between IPO5 and BMP but not TGF-beta R-SMADs. (PMID:27703004)
• The miR-378c-Samd1 circuit promotes phenotypic modulation of vascular smooth muscle cells and foam cells formation in atherosclerosis lesions. (PMID:34006929)
• SAMD1 attenuates antiphospholipid syndrome-induced pregnancy complications. (PMID:37904675)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	phc3	ENSDARG00000074604
danio_rerio	si:ch211-230g15.5	ENSDARG00000079167
danio_rerio	samd1a	ENSDARG00000102810

Paralogs (18): SCMH1 (ENSG00000010803), MBTD1 (ENSG00000011258), SCML1 (ENSG00000047634), L3MBTL2 (ENSG00000100395), SCML2 (ENSG00000102098), PHC1 (ENSG00000111752), THAP10 (ENSG00000129028), PHC2 (ENSG00000134686), SCML4 (ENSG00000146285), L3MBTL4 (ENSG00000154655), SFMBT1 (ENSG00000163935), PHC3 (ENSG00000173889), L3MBTL1 (ENSG00000185513), SAMD7 (ENSG00000187033), SAMD11 (ENSG00000187634), SFMBT2 (ENSG00000198879), L3MBTL3 (ENSG00000198945), SAMD13 (ENSG00000203943)

Protein

Protein identifiers

Sterile alpha motif domain-containing protein 1 — Q6SPF0 (reviewed: Q6SPF0)

Alternative names: Atherin

All UniProt accessions (2): E9PIW9, F8WDT5

UniProt curated annotations — full annotation on UniProt →

Function. Unmethylated CpG islands (CGIs)-binding protein which localizes to H3K4me3-decorated CGIs, where it acts as a transcriptional repressor. Tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs. Plays a role in atherogenesis by binding with LDL on cell surface and promoting LDL oxidation which leads to the formation of foam cell.

Subunit / interactions. Homopolymerize into a closed pentameric ring. Interacts (via SAM domain) with L3MBTL3 (via SAM domain); the interaction mediates L3MBTL3 binding to chromatin. Interacts (via WH domain) with KDM1A; the interaction modulates KDM1A function.

Subcellular location. Nucleus. Chromosome. Secreted.

Tissue specificity. Expressed in atherosclerotic lesions, not in normal intima. Expressed in foam cells.

Domain organisation. Winged-helix (WH) domain directly recognizes and binds unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove of DNA.

Induction. Expression is inhibited by miRNA MIR378C.

RefSeq proteins (1): NP_612361* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR048589	SAMD1-like_WH	Domain
IPR056983	SAMD1-like_SHD	Domain

Pfam: PF00536, PF21524, PF24971

UniProt features (40 total): compositionally biased region 11, helix 9, mutagenesis site 6, modified residue 3, region of interest 3, domain 2, strand 2, chain 1, sequence variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6LUJ	X-RAY DIFFRACTION	1.12
8Y77	X-RAY DIFFRACTION	1.5
6LUI	X-RAY DIFFRACTION	1.78
6LUK	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6SPF0-F1	63.55	0.24

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 (3): 107, 161, 261

Mutagenesis-validated functional residues (6):

Position	Phenotype
43	slightly decreases binding to unmethylated cpg islands.
45–46	strongly decreases binding to unmethylated cpg islands. abolishes interaction with kdm1a.
48	decreases binding to unmethylated cpg islands.
87–88	decreases binding to unmethylated cpg islands.
94	decreases binding to unmethylated cpg islands.
498–514	abolishes interaction with l3mbtl3.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 93 (showing top): GOBP_LIPID_MODIFICATION, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, BILD_E2F3_ONCOGENIC_SIGNATURE, TGIF_01, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER, GOBP_LIPID_METABOLIC_PROCESS, AACTTT_UNKNOWN, GOBP_REGULATION_OF_CHROMATIN_ORGANIZATION, GOBP_PROTEIN_HOMOOLIGOMERIZATION, DOUGLAS_BMI1_TARGETS_UP, GOBP_CHROMATIN_REMODELING

GO Biological Process (7): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin organization (GO:0006325), lipoprotein lipid oxidation (GO:0034439), protein homooligomerization (GO:0051260), foam cell differentiation (GO:0090077), negative regulation of transcription initiation-coupled chromatin remodeling (GO:0160217), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (4): DNA binding (GO:0003677), chromatin binding (GO:0003682), low-density lipoprotein particle binding (GO:0030169), protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cellular component organization	1
lipid oxidation	1
lipoprotein oxidation	1
protein complex oligomerization	1
cell differentiation	1
regulation of gene expression	1
transcription initiation-coupled chromatin remodeling	1
negative regulation of chromatin organization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
nucleic acid binding	1
lipoprotein particle binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1252 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SAMD1	SMAD4	Q13485	544
SAMD1	SMAD5	Q99717	487
SAMD1	RNF222	A6NCQ9	471
SAMD1	C19orf67	A6NJJ6	471
SAMD1	SAMD7	Q7Z3H4	361
SAMD1	ZNF676	Q8N7Q3	350
SAMD1	C19orf53	Q9UNZ5	348
SAMD1	DNAAF8	Q8IYS4	325
SAMD1	VSIG10L	Q86VR7	314
SAMD1	SAMHD1	Q9Y3Z3	301
SAMD1	YJU2B	P13994	297
SAMD1	BRME1	Q0VDD7	292
SAMD1	ZNF845	Q96IR2	290
SAMD1	SAMD4A	Q9UPU9	287
SAMD1	BMPR2	Q13873	272

IntAct

123 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
L3MBTL3	SAMD13	psi-mi:“MI:0914”(association)	0.640
PRMT2	SAMD1	psi-mi:“MI:0914”(association)	0.640
TOR1AIP2	TMEM223	psi-mi:“MI:0914”(association)	0.530
ANTXR1	POTEF	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
SKP2	DPYSL4	psi-mi:“MI:0914”(association)	0.530
DPPA4	ALOX12B	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
FAM9B	GEMIN2	psi-mi:“MI:0914”(association)	0.530
L3MBTL3	P4HA1	psi-mi:“MI:0914”(association)	0.530
KCNE3	RIOK3	psi-mi:“MI:0914”(association)	0.530
SAMD1	FXR1	psi-mi:“MI:0915”(physical association)	0.370
L3MBTL3		psi-mi:“MI:0914”(association)	0.350
NOP56	C12orf43	psi-mi:“MI:0914”(association)	0.350
HNRNPU		psi-mi:“MI:0914”(association)	0.350
SAMD1		psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
NCBP3	RSL1D1	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
HLA-DPA1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
VWA5A	PIPSL	psi-mi:“MI:0914”(association)	0.350

BioGRID (157): SAMD1 (Affinity Capture-MS), SAMD1 (Affinity Capture-MS), SAMD1 (Affinity Capture-MS), SAMD1 (Affinity Capture-MS), SAMD1 (Affinity Capture-MS), SAMD1 (Affinity Capture-MS), SAMD1 (Affinity Capture-MS), XIAP (Affinity Capture-MS), CLCN7 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), ECT2 (Affinity Capture-MS), NDUFB5 (Affinity Capture-MS), UPF1 (Affinity Capture-MS), SDCBP (Affinity Capture-MS), TLN1 (Affinity Capture-MS)

ESM2 similar proteins: A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A2VDX9, A6NIN4, D3YXK1, G3UXB3, O15370, O15522, O35392, O70218, O70220, O89113, P0DPE3, P12980, P17542, P22091, P28283, P82976, Q04890, Q05916, Q05917, Q13461, Q14V87, Q15270, Q19A40, Q5T230, Q5VY09, Q63244, Q6F5E0, Q6SPE9, Q6SPF0, Q7RTU7, Q80WY3, Q8TD94, Q8WY41, Q8WZ71, Q91XV7, Q96Q04

Diamond homologs: A2A5N8, B1B1A0, D3YUG0, D3YXK1, D3ZWK4, E1C2V1, O02274, O60284, O95251, P39769, P59178, P70047, P70475, P78364, P97500, Q01538, Q05BQ5, Q1JQD9, Q1RNF8, Q29L50, Q32N90, Q3MIF2, Q4V7W5, Q5DTW2, Q5R737, Q5SVQ0, Q5VUG0, Q5VXD3, Q64028, Q6DIN3, Q6P5G3, Q6SPE9, Q6SPF0, Q7Z3H4, Q80TY4, Q810T5, Q8BLB7, Q8C8Y5, Q8CFC2, Q8CHP6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	7
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

413 predictions. Top by Δscore:

Variant	Effect	Δscore
19:14088572:TTTC:T	acceptor_gain	1.0000
19:14088576:C:A	acceptor_loss	1.0000
19:14088577:T:G	acceptor_loss	1.0000
19:14088586:C:CT	acceptor_gain	1.0000
19:14088587:A:T	acceptor_gain	1.0000
19:14088666:CTCA:C	donor_loss	1.0000
19:14088667:TCAC:T	donor_loss	1.0000
19:14088668:CACC:C	donor_loss	1.0000
19:14088669:A:AC	donor_gain	1.0000
19:14088669:AC:A	donor_gain	1.0000
19:14088669:ACCTG:A	donor_gain	1.0000
19:14088670:C:CA	donor_gain	1.0000
19:14088670:CC:C	donor_gain	1.0000
19:14088670:CCTG:C	donor_gain	1.0000
19:14088670:CCTGC:C	donor_gain	1.0000
19:14088778:CGGGA:C	acceptor_gain	1.0000
19:14088779:GGGA:G	acceptor_gain	1.0000
19:14088780:GGA:G	acceptor_gain	1.0000
19:14088781:GA:G	acceptor_gain	1.0000
19:14088781:GACT:G	acceptor_loss	1.0000
19:14088783:C:CC	acceptor_gain	1.0000
19:14088786:C:CT	acceptor_gain	1.0000
19:14088787:A:T	acceptor_gain	1.0000
19:14088789:C:CT	acceptor_gain	1.0000
19:14088790:A:T	acceptor_gain	1.0000
19:14088794:C:CT	acceptor_gain	1.0000
19:14088795:A:T	acceptor_gain	1.0000
19:14088798:C:CT	acceptor_gain	1.0000
19:14088878:A:AC	donor_gain	1.0000
19:14088879:C:CC	donor_gain	1.0000

AlphaMissense

2748 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000525938 (19:14091050 C>A,G,T), RS1000575034 (19:14088357 T>C,G), RS1000807995 (19:14089633 A>C), RS1001908965 (19:14087919 G>A,C), RS1002309675 (19:14089808 T>A,C,G), RS1002476899 (19:14091374 G>A,T), RS1002591573 (19:14091217 C>T), RS1003081758 (19:14087370 C>G), RS1003130977 (19:14087589 A>G), RS1003174968 (19:14090609 A>G,T), RS1003478644 (19:14092460 G>C), RS1003595331 (19:14092163 C>T), RS1003918495 (19:14089540 T>C), RS1004536835 (19:14089439 G>A,C), RS1004765452 (19:14091696 T>A)

Disease associations

OMIM: gene MIM:620206 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
Air Pollutants	decreases expression, affects expression, increases abundance	2
Cadmium	decreases expression, increases abundance, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Ampicillin	increases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	decreases phosphorylation	1
Demecolcine	decreases expression	1
Lead	affects expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	decreases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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