ISM2

Summary

ISM2 (isthmin 2, HGNC:23176) is a protein-coding gene on chromosome 14q24.3, encoding Isthmin-2 (Q6H9L7).

The protein encoded by this gene contains a type 1 thrombospondin domain, which is present in thrombospondin, a number of proteins involved in the complement pathway, as well as in extracellular matrix proteins. Two alternatively spliced transcript variants encoding distinct isoforms have been observed.

Source: NCBI Gene 145501 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 110 total
• MANE Select transcript: NM_199296

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23176
Approved symbol	ISM2
Name	isthmin 2
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32147, TAIL1
Ensembl gene	ENSG00000100593
Ensembl biotype	protein_coding
OMIM	612684
Entrez	145501

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000216481, ENST00000342219, ENST00000471734, ENST00000472744, ENST00000480979, ENST00000487738, ENST00000493585, ENST00000554801, ENST00000892806

RefSeq mRNA: 2 — MANE Select: NM_199296 NM_182509, NM_199296

CCDS: CCDS45143, CCDS9864

Canonical transcript exons

ENST00000342219 — 7 exons

Exon	Start	End
ENSE00003459809	77474394	77476112
ENSE00003489000	77478242	77478325
ENSE00003497367	77484323	77484565
ENSE00003506522	77478575	77478715
ENSE00003604570	77484677	77484919
ENSE00003666707	77482322	77482667
ENSE00003676816	77498653	77498816

Expression profiles

Bgee: expression breadth ubiquitous, 115 present calls, max score 98.69.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.6279 / max 1393.4922, expressed in 140 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144234	3.5145	133
144235	0.0273	14
144231	0.0215	7
144233	0.0189	6
144236	0.0186	6
144232	0.0151	9
144230	0.0121	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	98.69	gold quality
placenta	UBERON:0001987	94.40	gold quality
pancreatic ductal cell	CL:0002079	76.91	silver quality
epithelial cell of pancreas	CL:0000083	73.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	71.93	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.08	silver quality
tibialis anterior	UBERON:0001385	69.06	silver quality
nasal cavity epithelium	UBERON:0005384	66.69	gold quality
upper arm skin	UBERON:0004263	63.93	gold quality
trabecular bone tissue	UBERON:0002483	63.67	gold quality
nucleus accumbens	UBERON:0001882	63.32	gold quality
parotid gland	UBERON:0001831	61.66	gold quality
upper leg skin	UBERON:0004262	61.39	gold quality
mucosa of stomach	UBERON:0001199	61.09	gold quality
endothelial cell	CL:0000115	60.62	gold quality
Brodmann (1909) area 46	UBERON:0006483	60.53	gold quality
myometrium	UBERON:0001296	60.52	gold quality
myocardium	UBERON:0002349	59.67	gold quality
cerebellar vermis	UBERON:0004720	59.10	gold quality
primary visual cortex	UBERON:0002436	58.82	gold quality
prostate gland	UBERON:0002367	58.77	gold quality
caudate nucleus	UBERON:0001873	58.27	gold quality
Brodmann (1909) area 23	UBERON:0013554	58.03	gold quality
corpus epididymis	UBERON:0004359	57.79	silver quality
putamen	UBERON:0001874	57.77	gold quality
skin of hip	UBERON:0001554	57.63	silver quality
occipital lobe	UBERON:0002021	57.60	gold quality
body of uterus	UBERON:0009853	57.45	gold quality
biceps brachii	UBERON:0001507	57.37	gold quality
cauda epididymis	UBERON:0004360	57.20	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	114.94
E-MTAB-6678	yes	18.03
E-ANND-3	no	2.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

95 targeting ISM2, 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-4425	100.00	67.59	1049
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 1)

• TAIL1 gene is located on chromosome 14q24.3 within ARVD1 (arrhythmogenic right ventricular dysplasia/cardiomyopathy, type 1) critical region; preliminary evidence suggests that it is expressed in several tissues, showing multiple alternative splicing. (PMID:15194193)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ism2	ENSMUSG00000050671
rattus_norvegicus	Ism2	ENSRNOG00000050312
caenorhabditis_elegans		WBGENE00017378
caenorhabditis_elegans		WBGENE00017379

Protein

Protein identifiers

Isthmin-2 — Q6H9L7 (reviewed: Q6H9L7)

Alternative names: Thrombospondin and AMOP domain-containing isthmin-like protein 1, Thrombospondin type-1 domain-containing protein 3

All UniProt accessions (4): Q6H9L7, G3V2Q2, H7C4M8, H7C5B3

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Tissue specificity. Expressed at high levels in the placenta and at moderate levels in the pancreas, kidney, heart, liver, lung, brain and skeletal muscle.

Similarity. Belongs to the isthmin family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q6H9L7-1	1	yes
Q6H9L7-2	2
Q6H9L7-3	3
Q6H9L7-4	4
Q6H9L7-5	5

RefSeq proteins (2): NP_872315, NP_954993* (*=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 (26 total): splice variant 6, glycosylation site 3, disulfide bond 3, region of interest 3, compositionally biased region 3, domain 2, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6H9L7-F1	55.86	0.18

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): 338–365, 342–370, 353–357

Glycosylation sites (3): 117, 300, 392

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 45 (showing top): chr14q24, MIYAGAWA_TARGETS_OF_EWSR1_ETS_FUSIONS_UP, PEDRIOLI_MIR31_TARGETS_UP, GSE13522_CTRL_VS_T_CRUZI_BRAZIL_STRAIN_INF_SKIN_UP, MIR106B_5P, MIR20A_5P, MIR106A_5P, MIR17_5P, MIR20B_5P, MIR93_5P, MIR526B_3P, MIR519D_3P, MIR15A_5P, MIR195_5P, MIR15B_5P

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1176 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISM2	MUC4	Q99102	809
ISM2	TGFB3	P10600	706
ISM2	SLIRP-OT1	Q8N769	528
ISM2	APPBP2	Q92624	492
ISM2	NOP53	Q9NZM5	436
ISM2	SAMD15	Q9P1V8	430
ISM2	SUSD2	Q9UGT4	415
ISM2	U2AF2	P26368	414
ISM2	NOXRED1	Q6NXP6	391
ISM2	PSG2	P11465	366
ISM2	PSG11	Q9UQ72	362
ISM2	CCDC85C	A6NKD9	349
ISM2	BTBD3	Q9Y2F9	349
ISM2	TASP1	Q9H6P5	348
ISM2	CCNK	O75909	348
ISM2	KIF16B	Q96L93	348

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ISM2	SCN3B	psi-mi:“MI:0915”(physical association)	0.560
ISM2	PEX1	psi-mi:“MI:0914”(association)	0.350
ISM2	SCN3B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): SCN3B (Two-hybrid), ISM2 (Affinity Capture-MS), GALNT2 (Affinity Capture-MS), PHLDB3 (Affinity Capture-MS), RSPRY1 (Affinity Capture-MS), PTRH2 (Affinity Capture-MS), DPY19L3 (Affinity Capture-MS), PEX1 (Affinity Capture-MS), CNPY4 (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), LRCH2 (Affinity Capture-MS), RPS3 (Affinity Capture-MS), DOCK7 (Affinity Capture-MS), LRCH4 (Affinity Capture-MS), BCHE (Affinity Capture-MS)

ESM2 similar proteins: A1L0T3, A1L4H1, A6QNY1, D3YZF7, O95428, P28698, P30203, P55068, P55106, P59222, P98162, Q04756, Q14767, Q28019, Q28062, Q28256, Q28343, Q28670, Q3U515, Q4G0T1, Q5F378, Q5HZW5, Q61003, Q61361, Q6H9L7, Q6KF10, Q6PGE4, Q6QNF4, Q7TQH7, Q7Z4F1, Q86T13, Q86VR7, Q86VZ4, Q8BV57, Q8BZE1, Q8CB67, Q8VCP9, Q8WTU2, Q91V98, Q96DN2

Diamond homologs: A2ATD1, A2VEC9, B1AKI9, B3EWY9, O60242, P07996, P35441, P35448, Q19204, Q28178, Q58T08, Q5EGE1, Q6H9L7, Q80ZF8, Q8CG65, Q8CGM1, Q8QFV1, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXF5, D3YXG0, D3Z7H8, D3ZTD8, E9Q6D8, F1LW30, G1FC92, G5ECS8, O08721, O08722, O08747, O14514, O15072, O60241, O95185, O95450, P07358, P10643, P11680

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	94
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1482 predictions. Top by Δscore:

Variant	Effect	Δscore
14:77476110:CAT:C	acceptor_gain	1.0000
14:77476111:ATCTG:A	acceptor_loss	1.0000
14:77476113:C:CA	acceptor_loss	1.0000
14:77476113:C:CC	acceptor_gain	1.0000
14:77476124:C:CT	acceptor_gain	1.0000
14:77476124:C:T	acceptor_gain	1.0000
14:77478238:TCAC:T	donor_loss	1.0000
14:77478239:CACC:C	donor_loss	1.0000
14:77478240:A:AC	donor_gain	1.0000
14:77478240:AC:A	donor_gain	1.0000
14:77478241:C:CT	donor_gain	1.0000
14:77478241:CC:C	donor_gain	1.0000
14:77478241:CCTTG:C	donor_gain	1.0000
14:77478323:TGCC:T	acceptor_loss	1.0000
14:77478324:GCC:G	acceptor_loss	1.0000
14:77478326:C:CC	acceptor_gain	1.0000
14:77478326:C:G	acceptor_loss	1.0000
14:77478327:T:G	acceptor_loss	1.0000
14:77484566:C:CA	acceptor_loss	1.0000
14:77484566:C:CC	acceptor_gain	1.0000
14:77484671:TCTCA:T	donor_loss	1.0000
14:77484672:CTCAC:C	donor_loss	1.0000
14:77484673:TCA:T	donor_loss	1.0000
14:77484674:CACCT:C	donor_loss	1.0000
14:77484675:ACC:A	donor_loss	1.0000
14:77484676:C:CG	donor_loss	1.0000
14:77484702:A:AC	donor_gain	1.0000
14:77484703:A:C	donor_gain	1.0000
14:77484920:C:CC	acceptor_gain	1.0000
14:77476108:CACAT:C	acceptor_gain	0.9900

AlphaMissense

3721 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:77475946:C:A	W455C	0.991
14:77475946:C:G	W455C	0.991
14:77475700:C:A	W537C	0.988
14:77475700:C:G	W537C	0.988
14:77475800:C:A	G504V	0.986
14:77475713:C:G	C533S	0.985
14:77475714:A:T	C533S	0.985
14:77475702:A:G	W537R	0.983
14:77475702:A:T	W537R	0.983
14:77478693:C:A	W332C	0.983
14:77478693:C:G	W332C	0.983
14:77475801:C:A	G504C	0.982
14:77475948:A:G	W455R	0.982
14:77475948:A:T	W455R	0.982
14:77475801:C:G	G504R	0.980
14:77476090:C:A	W407C	0.980
14:77476090:C:G	W407C	0.980
14:77475721:C:A	W530C	0.979
14:77475721:C:G	W530C	0.979
14:77475952:G:C	F453L	0.979
14:77475952:G:T	F453L	0.979
14:77475954:A:G	F453L	0.979
14:77475629:T:C	Y561C	0.974
14:77475887:C:G	C475S	0.974
14:77475888:A:T	C475S	0.974
14:77475886:G:C	C475W	0.972
14:77475656:C:G	C552S	0.971
14:77475657:A:T	C552S	0.971
14:77475713:C:T	C533Y	0.971
14:77475714:A:G	C533R	0.971

dbSNP variants (sampled 300 via entrez): RS1000075705 (14:77480865 A>C), RS1000086317 (14:77480968 C>T), RS1000115658 (14:77487290 A>G), RS1000126243 (14:77481061 C>T), RS1000333108 (14:77475232 C>G,T), RS1000468052 (14:77487110 T>C), RS1000725773 (14:77474929 C>T), RS1000742137 (14:77477545 C>T), RS1000906936 (14:77490715 C>A,G,T), RS1000918174 (14:77490959 G>C), RS1001080408 (14:77479138 C>G), RS1001112599 (14:77497412 C>A), RS1001158321 (14:77490678 G>A), RS1001234980 (14:77481644 TCA>T), RS1001287226 (14:77481980 G>A)

Disease associations

OMIM: gene MIM:612684 | disease phenotypes: MIM:613640

GenCC curated gene-disease

Mondo (1): neuropathy, hereditary sensory and autonomic, type 1C (MONDO:0013337)

Orphanet (1): Hereditary sensory and autonomic neuropathy type 1 (Orphanet:36386)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004613_39	Sum neutrophil eosinophil counts	2.000000e-12
GCST004629_137	Neutrophil count	3.000000e-12
GCST004633_32	Neutrophil percentage of white cells	5.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	decreases expression	2
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects splicing, decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Pioglitazone	increases expression	1
Zoledronic Acid	decreases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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