CISD2

Summary

CISD2 (CDGSH iron sulfur domain 2, HGNC:24212) is a protein-coding gene on chromosome 4q24, encoding CDGSH iron-sulfur domain-containing protein 2 (Q8N5K1). Regulator of autophagy that contributes to antagonize BECN1-mediated cellular autophagy at the endoplasmic reticulum.

The protein encoded by this gene is a zinc finger protein that localizes to the endoplasmic reticulum. The encoded protein binds an iron/sulfur cluster and may be involved in calcium homeostasis. Defects in this gene are a cause of Wolfram syndrome 2.

Source: NCBI Gene 493856 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Wolfram syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 84 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 51
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001008388

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24212
Approved symbol	CISD2
Name	CDGSH iron sulfur domain 2
Location	4q24
Locus type	gene with protein product
Status	Approved
Aliases	Miner1, ERIS, NAF-1
Ensembl gene	ENSG00000145354
Ensembl biotype	protein_coding
OMIM	611507
Entrez	493856

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 nonsense_mediated_decay

ENST00000273986, ENST00000503643, ENST00000574446, ENST00000643561, ENST00000646632, ENST00000895599, ENST00000912010

RefSeq mRNA: 1 — MANE Select: NM_001008388 NM_001008388

CCDS: CCDS34040

Canonical transcript exons

ENST00000273986 — 3 exons

Exon	Start	End
ENSE00003499066	102885216	102885430
ENSE00003824063	102887341	102892807
ENSE00003835185	102868992	102869187

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 97.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.6781 / max 377.7935, expressed in 1815 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49106	25.0218	1807
49108	2.9076	1423
49107	2.4705	1342
49109	1.1213	500
49105	0.1569	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	97.20	gold quality
oviduct epithelium	UBERON:0004804	96.79	gold quality
tendon of biceps brachii	UBERON:0008188	96.74	gold quality
islet of Langerhans	UBERON:0000006	95.61	gold quality
medial globus pallidus	UBERON:0002477	94.41	gold quality
pons	UBERON:0000988	93.29	gold quality
globus pallidus	UBERON:0001875	93.23	gold quality
cerebellar vermis	UBERON:0004720	93.09	gold quality
right lobe of liver	UBERON:0001114	92.94	gold quality
pancreatic ductal cell	CL:0002079	92.59	gold quality
esophagus squamous epithelium	UBERON:0006920	92.42	gold quality
kidney epithelium	UBERON:0004819	92.35	gold quality
adrenal tissue	UBERON:0018303	92.32	gold quality
pancreas	UBERON:0001264	91.94	gold quality
bone marrow cell	CL:0002092	91.82	gold quality
liver	UBERON:0002107	91.80	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.60	gold quality
rectum	UBERON:0001052	91.21	gold quality
hypothalamus	UBERON:0001898	91.18	gold quality
bone marrow	UBERON:0002371	91.13	gold quality
prefrontal cortex	UBERON:0000451	91.02	gold quality
stromal cell of endometrium	CL:0002255	90.99	gold quality
cortical plate	UBERON:0005343	90.93	gold quality
body of pancreas	UBERON:0001150	90.84	gold quality
anterior cingulate cortex	UBERON:0009835	90.81	gold quality
middle temporal gyrus	UBERON:0002771	90.76	gold quality
spinal cord	UBERON:0002240	90.69	gold quality
ileal mucosa	UBERON:0000331	90.66	gold quality
left adrenal gland	UBERON:0001234	90.48	gold quality
substantia nigra	UBERON:0002038	90.48	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	39.91
E-MTAB-10042	yes	23.38
E-MTAB-9221	yes	15.53
E-HCAD-10	no	2.44
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

206 targeting CISD2, 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-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 39)

• Novel mutation, new phenotypic variant with no diabetes insipidus, presence of peptic ulcer disease, platelet aggregation defect (PMID:14724730)
• A single missense mutation was identified in a novel, highly conserved zinc-finger gene, ZCD2, in three consanguineous families of Jordanian descent with Wolfram syndrome (WFS). (PMID:17846994)
• The authors show that Miner1 is a homodimer harboring two redox-active 2Fe-2S clusters, indicating for the first time an association of a redox-active FeS protein with Wolfram Syndrome 2. (PMID:19580816)
• NAF-1 is a BCL-2-associated co-factor that targets BCL-2 for antagonism of the autophagy pathway at the endoplasmic reticulum. (PMID:20010695)
• CISD2 has a role in lifespan control and disease [review] (PMID:20649540)
• NAF-1 as a previously unidentified cell target of anti-diabetes thiazolidinedione drugs. (PMID:23717386)
• Data show that the protein levels of NAF-1 (CISD2) and mNT (CISD1) are elevated in human epithelial breast cancer cells. (PMID:23959881)
• provides the first structural information, to our knowledge, for future targeting of the NAF-1-Bcl-2 complex in the regulation of apoptosis/autophagy in cancer biology (PMID:24706857)
• Studied the expression pattern and clinicopathological significance of CISD2 in patients with early-stage cervical cancer. (PMID:25134919)
• A novel CISD2 mutation is associated with wolfram syndrome 2. (PMID:25371195)
• The findings suggested that CISD2 haplotype-tagging single nucleotide polymorphisms are not associated with Alzheimer’s disease risk. (PMID:26154755)
• CISD2 exerts anti-apoptotic and anti-inflammatory effects in neural cells; and (2) curcumin can attenuate the downregulation of CISD2 in SCI and LPS-treated astrocytes. (PMID:26387034)
• High CISD2 expression was significantly associated with gastric cancer. (PMID:26565812)
• NAF-1 is a major player in the metabolic regulation of breast cancer cells. (PMID:26621032)
• CISD2 protein may serve as a candidate prognostic marker and a novel therapeutic target for hepatocellular carcinoma (HCC) and play an important role in promoting proliferation and enhanced progression of HCC. (PMID:26722601)
• CISD2 was up-regulated in laryngeal squamous cell carcinoma (PMID:27007153)
• CISD2 could be an independent prognostic factor for PC and suggested that the CISD2/Wnt/beta-catenin pathway contributed to the proliferation of PC and EMT (PMID:27983920)
• the patient that we describe in this report with the c.215A > G missense CISD2 variant had the classical features of Wolfram syndrome type 1. The c.215A > G (p.Asn72Ser) variant does not induce CISD2 RNA mis-splicing or a reduction in CISD2 protein levels. Thus, we report a novel missense homozygous CISD2 mutation in a patient with clinical features that differ from previously reported Wolfram syndrome 2 case reports. (PMID:28335035)
• CISD2 is down-regulated in gastric cancer, and its effects on the inhibition of cellular proliferation, metastatic ability, and increased chemotherapy sensitivity are mediated by antagonism to 5-FU-induced autophagy through the AKT/mTOR pathway. (PMID:28857517)
• upregulation of CISD2 is involved in an increased antioxidant capacity in response to elevated ROS levels during the formation and progression of lung adenocarcinoma. (PMID:28928421)
• CISD2 was increased in glioma samples and was associated with poor prognosis and aggressive tumor behavior. The miR449a/CISD2/beclin1mediated autophagy regulatory network contributed to the proliferation of glioma cells (PMID:28983596)
• CISD2 haploinsufficiency disrupts calcium homeostasis, causing ER stress and subsequent nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (PMID:29166610)
• The c.103 + 1G > A mutation resulted in the loss of functional CISD2 protein in the two Italian Wolfram syndrome type 2 patients. (PMID:29237418)
• CDGSH iron-sulfur domain-containing protein 2 (CISD2) Wolfram syndrome type 2 (WFS2) primary fibroblast cell lines showed consistent reduction in proliferation. (PMID:29239282)
• CDGSH Iron Sulfur Domain 2 Deficiency Inhibits Cell Proliferation and Induces Cell Differentiation of Neuroblastoma. (PMID:31642036)
• Neuronal CISD2 plays a minor anti-inflammatory role in LPS-stimulated neuron-like SH-SY5Y cells. (PMID:31683052)
• Cisd2: a promising new target in Alzheimer’s disease(dagger). (PMID:32207855)
• Elevated CISD2 expression predicts poor diagnosis and promotes invasion and migration of prostate cancer cells. (PMID:32633348)
• CISD2 maintains cellular homeostasis. (PMID:33422617)
• The NFkappaB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases. (PMID:33477809)
• CISD2 plays a role in age-related diseases and cancer. (PMID:33752060)
• Disrupting CISD2 function in cancer cells primarily impacts mitochondrial labile iron levels and triggers TXNIP expression. (PMID:34547371)
• Cisd2 plays an essential role in corneal epithelial regeneration. (PMID:34740104)
• CDGSH iron sulfur domain 2 mitigates apoptosis, oxidative stress and inflammatory response caused by oxygen-glucose deprivation/reoxygenation in HT22 hippocampal neurons by Akt-Nrf2-activated pathway. (PMID:35819709)
• CISD2 promotes lung squamous carcinoma cell migration and invasion via the TGF-beta1-induced Smad2/3 signaling pathway. (PMID:37249759)
• A preliminary study unveils CISD2 as a ferroptosis-related therapeutic target for recurrent spontaneous abortion through immunological analysis and two-sample mendelian randomization. (PMID:38678819)
• Overexpression of CISD2 alleviates septic acute kidney injury via activating Sonic Hedgehog signaling pathway. (PMID:38814213)
• CISD2 downregulation participates in the ferroptosis process of human ovarian SKOV-3 cells through modulating the wild type p53-mediated GLS2/SAT1/SLC7A11 and Gpx4/TRF signaling pathway. (PMID:38991271)
• CISD2 regulates oxidative stress and mitophagy to maintain the balance of the follicular microenvironment in PCOS. (PMID:39010730)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cisd2	ENSDARG00000052703
mus_musculus	Cisd2	ENSMUSG00000028165
rattus_norvegicus	Cisd2	ENSRNOG00000048258
drosophila_melanogaster	Cisd2	FBGN0062442
caenorhabditis_elegans		WBGENE00044026

Paralogs (2): CISD1 (ENSG00000122873), CISD3 (ENSG00000277972)

Protein

Protein identifiers

CDGSH iron-sulfur domain-containing protein 2 — Q8N5K1 (reviewed: Q8N5K1)

Alternative names: Endoplasmic reticulum intermembrane small protein, MitoNEET-related 1 protein, Nutrient-deprivation autophagy factor-1

All UniProt accessions (5): A0A2R8Y4Y3, A0A2R8Y540, D6RCF4, I3L1N9, Q8N5K1

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of autophagy that contributes to antagonize BECN1-mediated cellular autophagy at the endoplasmic reticulum. Participates in the interaction of BCL2 with BECN1 and is required for BCL2-mediated depression of endoplasmic reticulum Ca(2+) stores during autophagy. Contributes to BIK-initiated autophagy, while it is not involved in BIK-dependent activation of caspases. Involved in life span control, probably via its function as regulator of autophagy.

Subunit / interactions. Homodimer. Interacts with BCL2; the interaction is direct and disrupted by BIK interaction with BCL2. Interacts with BCL2L1. Interacts with ITPR1.

Subcellular location. Endoplasmic reticulum membrane. Mitochondrion outer membrane.

Tissue specificity. Testis, small intestine, kidney, lung, brain, heart, pancreas and platelets.

Disease relevance. Wolfram syndrome 2 (WFS2) [MIM:604928] A rare disorder characterized by juvenile-onset insulin-dependent diabetes mellitus with optic atrophy. Other manifestations include diabetes insipidus, sensorineural deafness, dementia, psychiatric illnesses. WFS2 patients additionally show a strong bleeding tendency and gastrointestinal ulceration. Diabetes insipidus may be absent. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [2Fe-2S] cluster.

Similarity. Belongs to the CISD protein family. CISD2 subfamily.

RefSeq proteins (1): NP_001008389* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018967	FeS-contain_CDGSH-typ	Domain
IPR019610	FeS-contain_mitoNEET_N	Domain
IPR042216	MitoNEET_CISD	Homologous_superfamily
IPR045131	CISD1/2	Family

Pfam: PF09360, PF10660

UniProt features (22 total): mutagenesis site 5, strand 4, binding site 4, turn 2, helix 2, topological domain 2, initiator methionine 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4OOA	X-RAY DIFFRACTION	1.58
4OO7	X-RAY DIFFRACTION	1.65
7P0P	X-RAY DIFFRACTION	1.74
3FNV	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N5K1-F1	90.19	0.64

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 (4): 99; 101; 110; 114

Mutagenesis-validated functional residues (5):

Position	Phenotype
99	impairs interaction with bcl2; when associated with s-101; s-110 and q-114.
101	impairs interaction with bcl2; when associated with s-99; s-110 and q-114.
110	impairs interaction with bcl2; when associated with s-99; s-101 and q-114.
114	impairs interaction with bcl2; when associated with s-99; s-101 and s-110.
92	has the same optical signature of the native protein and improves yields of purified protein and a decreased tendency to

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 226 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, chr4q24, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, WEI_MYCN_TARGETS_WITH_E_BOX, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOCC_MITOCHONDRIAL_ENVELOPE, DODD_NASOPHARYNGEAL_CARCINOMA_UP, FISCHER_DREAM_TARGETS, GOCC_PERINUCLEAR_ENDOPLASMIC_RETICULUM, MARSON_BOUND_BY_FOXP3_STIMULATED, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOCC_ORGANELLE_SUBCOMPARTMENT, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY

GO Biological Process (3): autophagy of mitochondrion (GO:0000422), regulation of autophagy (GO:0010506), autophagy (GO:0006914)

GO Molecular Function (6): RNA binding (GO:0003723), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), 2 iron, 2 sulfur cluster binding (GO:0051537), protein binding (GO:0005515), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (9): mitochondrial outer membrane (GO:0005741), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), protein-containing complex (GO:0032991), perinuclear endoplasmic reticulum (GO:0097038), cytoplasm (GO:0005737), mitochondrion (GO:0005739), intracellular membrane-bounded organelle (GO:0043231)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
autophagy	2
cytoplasm	2
intracellular membrane-bounded organelle	2
intracellular anatomical structure	2
regulation of catabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
nucleic acid binding	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
iron-sulfur cluster binding	1
binding	1
metal cluster binding	1
mitochondrial membrane	1
organelle outer membrane	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular_component	1
endoplasmic reticulum	1
perinuclear region of cytoplasm	1
membrane-bounded organelle	1
intracellular organelle	1

Protein interactions and networks

STRING

1304 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CISD2	CISD3	P0C7P0	962
CISD2	WFS1	O76024	946
CISD2	BECN1	Q14457	779
CISD2	GIMAP5	Q96F15	642
CISD2	BCL2	P10415	620
CISD2	HDAC8	Q9BY41	577
CISD2	PIK3R4	Q99570	508
CISD2	ITPR3	Q14573	492
CISD2	CANX	P27824	490
CISD2	UVRAG	Q9P2Y5	486
CISD2	BIK	Q13323	480
CISD2	ITPR1	Q14643	466
CISD2	MNT	Q99583	448
CISD2	CIAPIN1	Q6FI81	442
CISD2	NFS1	Q9Y697	425

IntAct

361 interactions, top by confidence:

A	B	Type	Score
HLA-C	HLA-A	psi-mi:“MI:0914”(association)	0.670
STIM2	PRKAB2	psi-mi:“MI:0914”(association)	0.640
EMD	CISD2	psi-mi:“MI:0915”(physical association)	0.560
LEPROTL1	CISD2	psi-mi:“MI:0915”(physical association)	0.560
PGAP2	CISD2	psi-mi:“MI:0915”(physical association)	0.560
SNORC	CISD2	psi-mi:“MI:0915”(physical association)	0.560
BMP10	CISD2	psi-mi:“MI:0915”(physical association)	0.560
FAM241B	CISD2	psi-mi:“MI:0915”(physical association)	0.560
CFHR5	CISD2	psi-mi:“MI:0915”(physical association)	0.560
POMGNT1	CISD2	psi-mi:“MI:0915”(physical association)	0.560
CISD2	PNKP	psi-mi:“MI:0915”(physical association)	0.560
EHHADH	CISD2	psi-mi:“MI:0915”(physical association)	0.560
TTPA	CISD2	psi-mi:“MI:0915”(physical association)	0.560
MIP	CISD2	psi-mi:“MI:0915”(physical association)	0.560
CISD2	CFHR5	psi-mi:“MI:0915”(physical association)	0.560
GAST	CISD2	psi-mi:“MI:0915”(physical association)	0.560
CISD2	SLC35B4	psi-mi:“MI:0915”(physical association)	0.560
SMIM1	CISD2	psi-mi:“MI:0915”(physical association)	0.560
CISD2	NAPB	psi-mi:“MI:0915”(physical association)	0.560
STX12	CISD2	psi-mi:“MI:0915”(physical association)	0.560
CISD2	HHATL	psi-mi:“MI:0915”(physical association)	0.560
TMEM187	CISD2	psi-mi:“MI:0915”(physical association)	0.560
CISD2	SERP2	psi-mi:“MI:0915”(physical association)	0.560
CISD2	CYBC1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (322): CISD2 (Affinity Capture-MS), CISD2 (Affinity Capture-MS), CISD2 (Affinity Capture-MS), CISD2 (Affinity Capture-MS), CISD2 (Affinity Capture-MS), CISD2 (Affinity Capture-MS), CISD2 (Co-fractionation), CISD2 (Co-fractionation), CISD2 (Co-fractionation), CISD2 (Co-fractionation), CISD2 (Proximity Label-MS), CISD2 (Proximity Label-MS), CISD2 (Proximity Label-MS), CISD2 (Affinity Capture-MS), CISD2 (Affinity Capture-MS)

ESM2 similar proteins: A8NJ91, A8WTH5, B1WC88, B4R3W7, C1BY38, O01323, O14068, O97172, P0C6K4, P0C6K7, P34310, P34535, P38837, P52870, P52871, P53224, Q05B71, Q06144, Q08176, Q16EE5, Q3ZN07, Q4TWH9, Q5I027, Q5NDN0, Q67726, Q6AZG1, Q6PCF8, Q6R7E9, Q7PSY2, Q80KJ8, Q8J0M4, Q8J0N0, Q8K190, Q8LE10, Q8N5K1, Q91WE4, Q9CQB5, Q9CZB9, Q9CZJ9, Q9H819

Diamond homologs: B0K020, B3M1H7, B3P5J1, B3RML8, B4GPI0, B4HZ81, B4JYJ2, B4K5X8, B4MBU8, B4NFN4, B4PQ50, B4QZI8, B5X8S2, B9EPI1, C1BGG0, C1BI29, C1C524, C3ZWH9, C4A0P0, Q05B71, Q29BX8, Q3ZBU2, Q5I027, Q6AZG1, Q6PCF8, Q7T326, Q8N5K1, Q91WS0, Q9CQB5, Q9FLI7, Q9NZ45, Q9VAM6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	31
Likely benign	34
Benign	2

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1456123	NC_000004.11:g.(?101947022)(104640832_?)del	Pathogenic
156218	NM_001008388.4(CISD2):c.(104_304)-84_318+724del	Pathogenic
2573447	NC_000004.11:g.(103790345_103806372)(103813965?)del	Pathogenic
3246712	NC_000004.11:g.(?103790242)(103806607_?)del	Pathogenic
638297	NM_001008388.5(CISD2):c.103+1G>A	Pathogenic
892	NM_001008388.5(CISD2):c.109G>C (p.Glu37Gln)	Pathogenic
3589720	NM_001008388.5(CISD2):c.109G>T (p.Glu37Ter)	Likely pathogenic

SpliceAI

376 predictions. Top by Δscore:

Variant	Effect	Δscore
4:102869184:ACAG:A	donor_loss	1.0000
4:102869185:CAG:C	donor_loss	1.0000
4:102869186:AG:A	donor_loss	1.0000
4:102869188:GT:G	donor_loss	1.0000
4:102869189:T:A	donor_loss	1.0000
4:102887339:A:AG	acceptor_gain	1.0000
4:102887340:G:GG	acceptor_gain	1.0000
4:102885314:G:GT	donor_gain	0.9900
4:102885345:A:T	donor_gain	0.9900
4:102885357:T:TA	donor_gain	0.9900
4:102885358:A:AA	donor_gain	0.9900
4:102887335:TTTTA:T	acceptor_loss	0.9900
4:102887336:TTTA:T	acceptor_loss	0.9900
4:102887338:TAGTT:T	acceptor_loss	0.9900
4:102887340:G:GT	acceptor_loss	0.9900
4:102887340:GTTT:G	acceptor_gain	0.9900
4:102887340:GTTTC:G	acceptor_gain	0.9900
4:102885344:G:GT	donor_gain	0.9800
4:102885353:A:T	donor_gain	0.9800
4:102885429:CGGT:C	donor_loss	0.9800
4:102885432:T:A	donor_loss	0.9800
4:102887340:GT:G	acceptor_gain	0.9800
4:102885211:TTTAG:T	acceptor_loss	0.9700
4:102885212:TTAGT:T	acceptor_loss	0.9700
4:102885215:G:GT	acceptor_gain	0.9700
4:102885315:A:T	donor_gain	0.9700
4:102885431:G:GG	donor_gain	0.9700
4:102887340:GTT:G	acceptor_gain	0.9700
4:102885209:T:G	acceptor_loss	0.9600
4:102885216:TTT:T	acceptor_loss	0.9600

AlphaMissense

874 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:102885328:T:A	N72K	1.000
4:102885328:T:G	N72K	1.000
4:102885407:T:C	C99R	1.000
4:102885411:G:C	R100T	1.000
4:102885411:G:T	R100M	1.000
4:102885412:G:C	R100S	1.000
4:102885412:G:T	R100S	1.000
4:102885413:T:C	C101R	1.000
4:102885416:T:A	W102R	1.000
4:102885416:T:C	W102R	1.000
4:102885418:G:C	W102C	1.000
4:102885418:G:T	W102C	1.000
4:102887341:T:C	F107L	1.000
4:102887343:T:A	F107L	1.000
4:102887343:T:G	F107L	1.000
4:102887350:T:C	C110R	1.000
4:102887389:G:C	D123H	1.000
4:102887390:A:T	D123V	1.000
4:102887399:G:A	G126D	1.000
4:102885326:A:G	N72D	0.999
4:102885343:G:C	K77N	0.999
4:102885343:G:T	K77N	0.999
4:102885407:T:A	C99S	0.999
4:102885408:G:A	C99Y	0.999
4:102885408:G:C	C99S	0.999
4:102885408:G:T	C99F	0.999
4:102885409:T:G	C99W	0.999
4:102885410:A:G	R100G	0.999
4:102885413:T:A	C101S	0.999
4:102885414:G:C	C101S	0.999

dbSNP variants (sampled 300 via entrez): RS1000101061 (4:102869232 A>T), RS1000293161 (4:102878582 C>G), RS1000355223 (4:102887951 A>C), RS1000442648 (4:102871937 T>C), RS1000465636 (4:102880647 C>A), RS1000586156 (4:102876710 A>G), RS1000857214 (4:102872163 G>C), RS10009572 (4:102886595 T>A), RS1001072518 (4:102883926 C>G), RS1001152347 (4:102868893 C>A), RS1001158376 (4:102868235 A>C,G), RS1001420760 (4:102883613 T>C), RS1001622363 (4:102872444 G>T), RS1001801111 (4:102887174 G>C), RS1001944345 (4:102870317 T>A)

Disease associations

OMIM: gene MIM:611507 | disease phenotypes: MIM:604928, MIM:248510

GenCC curated gene-disease

Disease	Classification	Inheritance
Wolfram syndrome 2	Definitive	Autosomal recessive
Wolfram syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Wolfram syndrome	Definitive	AR

Mondo (3): Wolfram syndrome 2 (MONDO:0011502), beta-mannosidosis (MONDO:0009562), Wolfram syndrome (MONDO:0018105)

Orphanet (2): Wolfram syndrome (Orphanet:3463), Beta-mannosidosis (Orphanet:118)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000011	Neurogenic bladder
HP:0000026	Male hypogonadism
HP:0000079	Abnormality of the urinary system
HP:0000112	Nephropathy
HP:0000135	Hypogonadism
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000726	Dementia
HP:0000738	Hallucinations
HP:0000786	Primary amenorrhea
HP:0000819	Diabetes mellitus
HP:0000823	Delayed puberty
HP:0000873	Diabetes insipidus
HP:0000876	Oligomenorrhea
HP:0001138	Optic neuropathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001387	Joint stiffness
HP:0001638	Cardiomyopathy
HP:0001892	Abnormal bleeding
HP:0001903	Anemia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003129_19	Primary biliary cholangitis	8.000000e-10
GCST004894_89	Type 2 diabetes	7.000000e-09
GCST004946_70	Schizophrenia	3.000000e-08
GCST008059_76	Estimated glomerular filtration rate	3.000000e-21
GCST008919_4	Asthma and attention deficit hyperactivity disorder	3.000000e-08

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D014929	Wolfram Syndrome	C09.218.458.341.186.500.750; C10.292.700.225.500.980; C10.574.500.662.980; C10.597.751.418.341.186.500.750; C10.597.751.941.162.625.750; C11.270.564.980; C11.640.451.451.980; C11.966.075.375.750; C12.050.351.968.419.135.875; C12.200.777.419.135.875; C12.950.419.135.875; C16.131.077.299.750; C16.320.290.564.980; C16.320.400.630.980; C18.452.394.750.124.960; C19.246.267.960; C19.700.159.875
D044905	beta-Mannosidosis	C16.320.565.202.607.750; C16.320.565.595.577.750; C18.452.648.202.607.750; C18.452.648.595.577.750
C565733	Wolfram Syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523399 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 115,979 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL121	ROSIGLITAZONE	4	58,849
CHEMBL595	PIOGLITAZONE	4	57,130

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

ChEMBL bioactivities

36 potent at pChembl≥5 of 37 total, top 36 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	EC50	10	nM	CHEMBL5624947
7.92	EC50	12	nM	CHEMBL5630437
7.64	EC50	23	nM	CHEMBL5629957
7.47	EC50	34	nM	CHEMBL5630422
7.46	EC50	35	nM	CHEMBL5624969
7.46	EC50	35	nM	CHEMBL5625079
7.34	EC50	46	nM	CHEMBL5624914
7.23	Kd	59.12	nM	CHEMBL5653589
7.23	ED50	59.12	nM	CHEMBL5653589
7.09	EC50	82	nM	CHEMBL5624927
7.02	EC50	95	nM	CHEMBL5624672
6.82	EC50	153	nM	CHEMBL5624481
6.80	EC50	160	nM	CHEMBL5629934
6.79	EC50	164	nM	CHEMBL5630099
6.72	EC50	191	nM	CHEMBL5630832
6.71	EC50	197	nM	CHEMBL5625084
6.63	EC50	233	nM	CHEMBL5631163
6.60	EC50	252	nM	CHEMBL5630818
6.53	EC50	296	nM	CHEMBL5630339
6.26	EC50	553	nM	CHEMBL5624858
6.18	EC50	661	nM	CHEMBL5631070
6.09	EC50	809	nM	CHEMBL5624588
6.01	EC50	979	nM	CHEMBL5630187
5.87	EC50	1345	nM	CHEMBL5630368
5.82	EC50	1520	nM	CHEMBL5630567
5.80	EC50	1585	nM	CHEMBL5631064
5.77	EC50	1701	nM	CHEMBL5624482
5.68	EC50	2085	nM	CHEMBL5629851
5.66	EC50	2179	nM	CHEMBL5624604
5.64	IC50	2290	nM	ROSIGLITAZONE
5.57	EC50	2667	nM	CHEMBL5625010
5.51	EC50	3072	nM	CHEMBL5629918
5.51	Kd	3104	nM	CHEMBL3752910
5.51	ED50	3104	nM	CHEMBL3752910
5.35	EC50	4444	nM	CHEMBL5624567
5.32	IC50	4800	nM	PIOGLITAZONE

PubChem BioAssay actives

34 with measured affinity, of 48 total; 34 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
methyl 2-amino-4-methyl-5-[(4-methylphenyl)carbamoyl]thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0100	uM
methyl 2-amino-5-[(4-methoxyphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0120	uM
methyl 2-amino-5-[(3-methoxyphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0230	uM
methyl 2-amino-5-[(4-fluorophenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0340	uM
methyl 2-amino-4-methyl-5-[(3-methylphenyl)carbamoyl]thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0350	uM
methyl 2-amino-5-[[4-(dimethylamino)phenyl]carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0350	uM
methyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0460	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148073: Binding affinity to human CISD2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0591	uM
methyl 2-amino-5-[(4-cyanophenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0820	uM
methyl 2-amino-4-methyl-5-(phenylcarbamoyl)thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.0950	uM
methyl 2-amino-4-methyl-5-(1,3-thiazol-2-ylcarbamoyl)thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.1530	uM
4-acetyl-5-amino-N-(4-fluorophenyl)-3-methylthiophene-2-carboxamide	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.1600	uM
4-acetyl-5-amino-N-(2,4-dimethylphenyl)-3-methylthiophene-2-carboxamide	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.1640	uM
methyl 2-amino-5-[(4-hydroxyphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.1910	uM
ethyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.1970	uM
methyl 2-amino-4-methyl-5-[(2-methylphenyl)carbamoyl]thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.2330	uM
methyl 2-amino-4-methyl-5-[[4-(trifluoromethyl)phenyl]carbamoyl]thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.2520	uM
2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylic acid	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.2960	uM
4-acetyl-5-amino-3-methyl-N-phenylthiophene-2-carboxamide	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.5530	uM
methyl 2-amino-4-methyl-5-(pyridin-3-ylcarbamoyl)thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.6610	uM
5-amino-N-(2,4-dimethylphenyl)-4-(2-hydroxyacetyl)-3-methylthiophene-2-carboxamide	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.8090	uM
5-amino-2-N-(2,4-dimethylphenyl)-3-methylthiophene-2,4-dicarboxamide	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	0.9790	uM
tert-butyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	1.3450	uM
propan-2-yl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	1.5200	uM
5-amino-4-N-(cyanomethyl)-2-N-(2,4-dimethylphenyl)-3-methylthiophene-2,4-dicarboxamide	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	1.5850	uM
methyl 2-amino-4-methyl-5-[(2,4,6-trimethylphenyl)carbamoyl]thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	1.7010	uM
methyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	2.0850	uM
methyl 2-amino-4-methyl-5-[(3,4,5-trimethoxyphenyl)carbamoyl]thiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	2.1790	uM
Rosiglitazone	1572805: Binding affinity to recombinant human N-terminal His6-tagged NAF1 expressed in Escherichia coli by scintillation proximity assay	ic50	2.2900	uM
5-amino-4-cyano-N-(2,4-dimethylphenyl)-3-methylthiophene-2-carboxamide	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	2.6670	uM
methyl 2-amino-5-[(2-methoxyphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	3.0720	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148073: Binding affinity to human CISD2 incubated for 45 mins by Kinobead based pull down assay	kd	3.1037	uM
methyl 2-acetamido-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate	2133872: Activation of Cisd2 (unknown origin) transfected in HEK293 cells incubated for 24 hrs by one-glo luciferase assay	ec50	4.4440	uM
Pioglitazone	1572805: Binding affinity to recombinant human N-terminal His6-tagged NAF1 expressed in Escherichia coli by scintillation proximity assay	ic50	4.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tunicamycin	increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
di-n-butylphosphoric acid	affects expression	1
bisphenol S	affects expression	1
bisphenol AF	increases expression	1
Vorinostat	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Rotenone	increases expression	1
Thimerosal	increases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4370834	Binding	Binding affinity to recombinant human N-terminal His6-tagged NAF1 expressed in Escherichia coli by scintillation proximity assay	Binding of thiazolidinediones to the endoplasmic reticulum protein nutrient-deprivation autophagy factor-1. — Bioorg Med Chem Lett

Cellosaurus cell lines

13 cell lines: 7 induced pluripotent stem cell, 4 finite cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A4FH	WFS2_1#2	Induced pluripotent stem cell	Female
CVCL_A4FI	WFS2_1#3	Induced pluripotent stem cell	Female
CVCL_A4FJ	WFS2_1#10	Induced pluripotent stem cell	Female
CVCL_A4FK	WFS2_1#11	Induced pluripotent stem cell	Female
CVCL_A4FL	WFS2_1#24	Induced pluripotent stem cell	Female
CVCL_A4FM	WFS2_3#1	Induced pluripotent stem cell	Male
CVCL_A4FN	WFS2_3#6	Induced pluripotent stem cell	Male
CVCL_A5DK	WFS2_4	Finite cell line	Female
CVCL_A5DL	WFS2_3	Finite cell line	Male
CVCL_A5DM	WFS2_2	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03717909	PHASE2	COMPLETED	Efficacy and Safety Trial of Sodium Valproate, in Paediatric and Adult Patients With Wolfram Syndrome
NCT04940572	PHASE2	UNKNOWN	Efficacy Study of Daily Administration of VPA in Patients Affected by Wolfram Syndrome
NCT05659368	PHASE2	UNKNOWN	Tirzepatide Monotherapy in Patients With Wolfram Syndrome Type 1
NCT05676034	PHASE2	ACTIVE_NOT_RECRUITING	AMX0035 in Adult Patients With Wolfram Syndrome
NCT02829268	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
NCT01302327	Not specified	WITHDRAWN	GLP Analogs for Diabetes in Wolfram Syndrome Patients
NCT02455414	Not specified	COMPLETED	Tracking Neurodegeneration in Early Wolfram Syndrome
NCT02841553	Not specified	RECRUITING	Wolfram Syndrome and WFS1-related Disorders International Registry and Clinical Study
NCT03951298	Not specified	COMPLETED	I-Tracking Neurodegeneration in Early Wolfram Syndrome
NCT03988764	Not specified	RECRUITING	Monogenic Diabetes Misdiagnosed as Type 1
NCT07313085	Not specified	NOT_YET_RECRUITING	Mechanisms of Fecal Incontinence in Wolfram Syndrome
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses