ISM1

Summary

ISM1 (isthmin 1, HGNC:16213) is a protein-coding gene on chromosome 20p12.1, encoding Isthmin-1 (B1AKI9). Acts as an angiogenesis inhibitor.

Predicted to be involved in negative regulation of angiogenesis. Predicted to be located in extracellular region.

Source: NCBI Gene 140862 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 97 total
• MANE Select transcript: NM_080826

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16213
Approved symbol	ISM1
Name	isthmin 1
Location	20p12.1
Locus type	gene with protein product
Status	Approved
Aliases	bA149I18.1
Ensembl gene	ENSG00000101230
Ensembl biotype	protein_coding
OMIM	615793
Entrez	140862

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000262487

RefSeq mRNA: 1 — MANE Select: NM_080826 NM_080826

CCDS: CCDS46579

Canonical transcript exons

ENST00000262487 — 6 exons

Exon	Start	End
ENSE00000859125	13270504	13270743
ENSE00000859126	13279634	13279898
ENSE00000859127	13288540	13288683
ENSE00000906769	13292374	13292463
ENSE00001549837	13221274	13221914
ENSE00001729252	13298942	13300651

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 94.28.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9046 / max 25.3386, expressed in 456 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183608	0.9046	456

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pericardium	UBERON:0002407	94.28	gold quality
right lobe of thyroid gland	UBERON:0001119	90.46	gold quality
left lobe of thyroid gland	UBERON:0001120	89.64	gold quality
skin of hip	UBERON:0001554	89.42	gold quality
thyroid gland	UBERON:0002046	88.93	gold quality
upper arm skin	UBERON:0004263	87.68	gold quality
placenta	UBERON:0001987	87.23	gold quality
mammary duct	UBERON:0001765	87.05	gold quality
epithelium of mammary gland	UBERON:0003244	86.88	gold quality
tendon of biceps brachii	UBERON:0008188	86.16	gold quality
popliteal artery	UBERON:0002250	85.81	gold quality
tibial artery	UBERON:0007610	85.78	gold quality
thoracic mammary gland	UBERON:0005200	84.76	gold quality
mammary gland	UBERON:0001911	84.61	gold quality
layer of synovial tissue	UBERON:0007616	84.25	gold quality
upper leg skin	UBERON:0004262	83.56	gold quality
aorta	UBERON:0000947	83.37	gold quality
zone of skin	UBERON:0000014	82.24	gold quality
skin of leg	UBERON:0001511	82.11	gold quality
buccal mucosa cell	CL:0002336	81.83	gold quality
skin of abdomen	UBERON:0001416	81.71	gold quality
descending thoracic aorta	UBERON:0002345	81.07	gold quality
calcaneal tendon	UBERON:0003701	80.97	gold quality
synovial joint	UBERON:0002217	80.88	gold quality
minor salivary gland	UBERON:0001830	80.80	gold quality
thoracic aorta	UBERON:0001515	80.56	gold quality
ascending aorta	UBERON:0001496	80.26	gold quality
tibia	UBERON:0000979	80.02	gold quality
mucosa of stomach	UBERON:0001199	79.45	gold quality
tendon	UBERON:0000043	79.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

72 targeting ISM1, 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-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-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4753-3P	99.90	71.03	3786

Literature-anchored findings (GeneRIF, showing 12)

• Isthmin unexpectedly has both a pro-survival and death-promoting effect on endothelial cells depending on its physical state. (PMID:21544092)
• Given that ISM1 has been reported to have anti-angiogenic properties, these observations suggest that ISM1 is a mediator of lymphocyte effector functions and may participate in both innate and acquired immune responses. (PMID:24956034)
• Our study demonstrates a successful pipeline from CNV identification of a candidate gene to functional validation in a vertebrate model system, and reveals Isthmin 1 as both a new human clefting locus as well as a key craniofacial patterning gene. (PMID:29162626)
• we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling. (PMID:31171630)
• MiR-1307-3p inhibited activation of Wnt3a/beta-catenin signaling through targeting downregulation of ISM1. (PMID:31513891)
• Regulation of N-glycosylation and secretion of Isthmin-1 by its C-mannosylation. (PMID:33412225)
• Isthmin 1 is Expressed by Progenitor-Like Cells in the Lung: Phenotypical Analysis of Isthmin 1(+) Hematopoietic Stem-Like Cells in Homeostasis and during Infection. (PMID:35402623)
• Serum isthmin-1 levels are positively and independently correlated with albuminuria in patients with type 2 diabetes mellitus. (PMID:36126993)
• The Angiogenesis Inhibitor Isthmin-1 (ISM1) Is Overexpressed in Experimental Models of Glomerulopathy and Impairs the Viability of Podocytes. (PMID:36769045)
• Investigation of serum isthmin 1 concentration in pregnant women diagnosed with gestational diabetes mellitus; a case-control study. (PMID:37852798)
• Isthmin: A multifunctional secretion protein. (PMID:37979212)
• Serum isthmin-1 is a potential biomarker for metabolic dysfunction associated fatty liver disease in patients with metabolic syndrome and type 2 diabetes mellitus. (PMID:39322582)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ism1	ENSDARG00000020541
mus_musculus	Ism1	ENSMUSG00000074766
rattus_norvegicus	Ism1	ENSRNOG00000063262
drosophila_melanogaster	Tsp	FBGN0031850

Paralogs (5): COMP (ENSG00000105664), THBS4 (ENSG00000113296), THBS1 (ENSG00000137801), THBS3 (ENSG00000169231), THBS2 (ENSG00000186340)

Protein

Protein identifiers

Isthmin-1 — B1AKI9 (reviewed: B1AKI9)

All UniProt accessions (1): B1AKI9

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an angiogenesis inhibitor.

Subunit / interactions. Interacts with integrin ITGAV/ITGB5.

Subcellular location. Secreted.

Domain organisation. The C-terminal AMOP domain plays an important role in the anti-angiogenic function of ISM1.

Similarity. Belongs to the isthmin family.

RefSeq proteins (1): NP_543016* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR005533	AMOP_dom	Domain
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR051867	Angio_Inhib/Adhesion_GPCR	Family

Pfam: PF00090, PF03782

UniProt features (15 total): disulfide bond 3, region of interest 3, compositionally biased region 3, domain 2, signal peptide 1, chain 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9C6T	X-RAY DIFFRACTION	3.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-B1AKI9-F1	65.01	0.29

Functional residue map

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

Disulfide bonds (3): 229–256, 233–261, 244–248

Glycosylation sites (1): 39

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 63 (showing top): DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_CIRCULATORY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_VASCULATURE_DEVELOPMENT, VECCHI_GASTRIC_CANCER_ADVANCED_VS_EARLY_UP, GOBP_TUBE_MORPHOGENESIS, LIM_MAMMARY_STEM_CELL_UP, GOBP_TUBE_DEVELOPMENT, ZNF513_TARGET_GENES, ZNF561_TARGET_GENES, ZNF92_TARGET_GENES, ZSCAN30_TARGET_GENES

GO Biological Process (1): negative regulation of angiogenesis (GO:0016525)

GO Molecular Function (0):

GO Cellular Component (1): extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISM1	CALN1	Q9BXU9	612
ISM1	SUSD2	Q9UGT4	498
ISM1	HSPA5	P11021	450
ISM1	ACKR4	Q9NPB9	409
ISM1	ARHGAP18	Q8N392	396
ISM1	FKBPL	Q9UIM3	396
ISM1	TSR1	Q2NL82	388
ISM1	BTBD3	Q9Y2F9	379
ISM1	TASP1	Q9H6P5	346
ISM1	HES3	Q5TGS1	336
ISM1	MMRN2	Q9H8L6	330
ISM1	MUC4	Q99102	329
ISM1	LDLRAD4	O15165	324
ISM1	MCRIP2	Q9BUT9	320
ISM1	TOP3B	O95985	318

IntAct

0 interactions, top by confidence:

BioGRID (2): ISM1 (Affinity Capture-RNA), ISM1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A088MLT8, A0JPH4, A2A8U2, A2ATD1, A6QLD2, B1AKI9, B1AL88, B3KU38, O14525, O35757, O75129, P0DPB3, P0DPB4, P12755, P17863, P27424, P49140, P55001, P55002, P85299, P97953, Q3V1G4, Q58CS8, Q5EGE1, Q5QQ56, Q5QQ57, Q60698, Q61137, Q68BL8, Q6DVA0, Q6L8S8, Q6L9W6, Q6S5C2, Q6ZWB6, Q80U62, Q80Z10, Q812A5, Q86Y38, Q8CCS2, Q8JG33

Diamond homologs: A2ATD1, A2VEC9, B1AKI9, B3EWY9, O60242, P07996, P35441, P35448, Q19204, Q28178, Q58T08, Q5EGE1, Q6H9L7, Q80ZF8, Q8CG65, Q8CGM1, Q8QFV1, D3YXG0, D3ZTD8, P16893, P35440, P35442, Q03350, Q13591, Q29RU4, Q62217, Q95116, Q9VTT0, C0HL12, O60241, Q3UHD1, Q5R7Y0, B3EWZ3, B3EWZ8, C5IAW9, E9Q6D8, F1LW30, G5ECS8, O08721, O08722

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	16
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

785 predictions. Top by Δscore:

Variant	Effect	Δscore
20:13221911:GCAG:G	donor_gain	1.0000
20:13270501:TAGAA:T	acceptor_loss	1.0000
20:13270502:A:AG	acceptor_gain	1.0000
20:13270502:A:T	acceptor_loss	1.0000
20:13270503:G:GT	acceptor_gain	1.0000
20:13270503:GA:G	acceptor_gain	1.0000
20:13270503:GAA:G	acceptor_gain	1.0000
20:13270503:GAAT:G	acceptor_gain	1.0000
20:13270503:GAATA:G	acceptor_gain	1.0000
20:13288681:CAGGT:C	donor_loss	1.0000
20:13288684:GTGC:G	donor_loss	1.0000
20:13288685:T:G	donor_loss	1.0000
20:13292460:GTTG:G	donor_gain	1.0000
20:13221910:TGCAG:T	donor_gain	0.9900
20:13221911:GCAGG:G	donor_gain	0.9900
20:13221915:G:GG	donor_gain	0.9900
20:13221916:T:G	donor_loss	0.9900
20:13279629:TTCA:T	acceptor_loss	0.9900
20:13279631:CA:C	acceptor_loss	0.9900
20:13279633:G:GT	acceptor_loss	0.9900
20:13286399:A:AG	donor_gain	0.9900
20:13288536:CCAG:C	acceptor_loss	0.9900
20:13288537:CAG:C	acceptor_loss	0.9900
20:13288684:G:GG	donor_gain	0.9900
20:13292459:AGTTG:A	donor_loss	0.9900
20:13292465:TAAGA:T	donor_loss	0.9900
20:13298940:A:AG	acceptor_gain	0.9900
20:13298941:G:GA	acceptor_gain	0.9900
20:13279632:A:AG	acceptor_gain	0.9800
20:13279633:G:GG	acceptor_gain	0.9800

AlphaMissense

3078 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:13288565:G:C	W223C	1.000
20:13288565:G:T	W223C	1.000
20:13288574:G:C	W226C	1.000
20:13288574:G:T	W226C	1.000
20:13298964:G:C	W300C	1.000
20:13298964:G:T	W300C	1.000
20:13299106:T:A	W348R	1.000
20:13299106:T:C	W348R	1.000
20:13299108:G:C	W348C	1.000
20:13299108:G:T	W348C	1.000
20:13299166:T:C	C368R	1.000
20:13299167:G:A	C368Y	1.000
20:13299168:C:G	C368W	1.000
20:13299219:C:G	C385W	1.000
20:13299340:T:C	C426R	1.000
20:13299341:G:A	C426Y	1.000
20:13299342:C:G	C426W	1.000
20:13288572:T:A	W226R	0.999
20:13288572:T:C	W226R	0.999
20:13288615:G:C	R240P	0.999
20:13288621:G:C	R242P	0.999
20:13288638:T:A	C248S	0.999
20:13288638:T:C	C248R	0.999
20:13288639:G:A	C248Y	0.999
20:13288639:G:C	C248S	0.999
20:13288640:C:G	C248W	0.999
20:13298953:T:A	C297S	0.999
20:13298954:G:A	C297Y	0.999
20:13298954:G:C	C297S	0.999
20:13298962:T:A	W300R	0.999

dbSNP variants (sampled 300 via entrez): RS1000007799 (20:13294674 C>G), RS1000015159 (20:13266777 A>C), RS1000092771 (20:13260687 G>A), RS1000122756 (20:13240974 T>C), RS1000133950 (20:13295858 C>G), RS1000134955 (20:13224330 A>G), RS1000218315 (20:13315127 A>G), RS1000226790 (20:13284048 C>T), RS1000234650 (20:13241314 A>G), RS1000307790 (20:13230265 G>A,C,T), RS1000393581 (20:13247900 G>T), RS1000399486 (20:13290446 G>A,C), RS1000420228 (20:13223428 G>C), RS1000420660 (20:13289671 G>A), RS1000442496 (20:13236277 A>C,G)

Disease associations

OMIM: gene MIM:615793 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000528_1	Parkinson’s disease	5.000000e-06
GCST002119_22	Metabolite levels (X-11787)	7.000000e-06
GCST002822_2	Survival in colon cancer	2.000000e-06
GCST003518_10	Daytime sleep phenotypes	3.000000e-07
GCST003518_12	Daytime sleep phenotypes	3.000000e-06
GCST003542_186	Night sleep phenotypes	8.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005276	hydroxy-leucine measurement
EFO:0000638	overall survival
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Estradiol	increases expression, affects cotreatment, decreases expression	3
entinostat	increases expression, affects cotreatment	2
Calcitriol	increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol A	affects methylation	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	increases methylation	1
Leflunomide	increases expression	1
Glyphosate	increases expression	1
Arsenic	increases methylation	1
Indomethacin	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Progesterone	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression, decreases methylation	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1G4	Abcam A-549 ISM1 KO 1	Cancer cell line	Male
CVCL_B2NN	Abcam A-549 ISM1 KO 2	Cancer cell line	Male

Clinical trials (associated diseases)

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