IGHMBP2

Summary

IGHMBP2 (immunoglobulin mu DNA binding protein 2, HGNC:5542) is a protein-coding gene on chromosome 11q13.3, encoding DNA-binding protein SMUBP-2 (P38935). 5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.

This gene encodes a helicase superfamily member that binds a specific DNA sequence from the immunoglobulin mu chain switch region. Mutations in this gene lead to spinal muscle atrophy with respiratory distress type 1.

Source: NCBI Gene 3508 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary peripheral neuropathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,507 total — 101 pathogenic, 43 likely-pathogenic
• Phenotypes (HPO): 47
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_002180

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5542
Approved symbol	IGHMBP2
Name	immunoglobulin mu DNA binding protein 2
Location	11q13.3
Locus type	gene with protein product
Status	Approved
Aliases	ZFAND7, SMUBP2, CATF1, SMARD1, HCSA, HMN6, CMT2S
Ensembl gene	ENSG00000132740
Ensembl biotype	protein_coding
OMIM	600502
Entrez	3508

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 24 protein_coding_CDS_not_defined, 17 nonsense_mediated_decay, 6 protein_coding, 5 retained_intron

ENST00000255078, ENST00000536803, ENST00000537458, ENST00000539064, ENST00000539224, ENST00000541229, ENST00000543739, ENST00000544521, ENST00000544541, ENST00000545146, ENST00000545475, ENST00000568742, ENST00000674583, ENST00000674597, ENST00000674672, ENST00000674675, ENST00000674698, ENST00000674729, ENST00000674745, ENST00000674775, ENST00000674878, ENST00000674955, ENST00000675118, ENST00000675119, ENST00000675142, ENST00000675205, ENST00000675305, ENST00000675310, ENST00000675389, ENST00000675464, ENST00000675469, ENST00000675493, ENST00000675615, ENST00000675648, ENST00000675674, ENST00000675683, ENST00000675684, ENST00000675755, ENST00000675800, ENST00000675873, ENST00000675916, ENST00000675964, ENST00000675997, ENST00000676083, ENST00000676149, ENST00000676173, ENST00000676182, ENST00000676228, ENST00000676239, ENST00000676240, ENST00000676400, ENST00000925063

RefSeq mRNA: 1 — MANE Select: NM_002180 NM_002180

CCDS: CCDS8187

Canonical transcript exons

ENST00000255078 — 15 exons

Exon	Start	End
ENSE00000737364	68914823	68915023
ENSE00001064263	68906069	68906238
ENSE00001117311	68917736	68917883
ENSE00001200438	68933299	68933481
ENSE00001200470	68903891	68904038
ENSE00002298832	68939534	68940601
ENSE00003484850	68908145	68908337
ENSE00003505066	68935299	68935422
ENSE00003533393	68934464	68934558
ENSE00003571333	68911440	68911603
ENSE00003593759	68933795	68933913
ENSE00003624384	68938182	68938354
ENSE00003639196	68929183	68929357
ENSE00003680499	68936237	68937091
ENSE00003693326	68908534	68908631

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 99.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2235 / max 136.2726, expressed in 1795 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115560	11.2235	1795

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	99.41	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.90	gold quality
lower esophagus	UBERON:0013473	95.86	gold quality
body of uterus	UBERON:0009853	95.60	gold quality
popliteal artery	UBERON:0002250	95.34	gold quality
tibial artery	UBERON:0007610	95.34	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.25	gold quality
aorta	UBERON:0000947	94.88	gold quality
ascending aorta	UBERON:0001496	94.75	gold quality
thoracic aorta	UBERON:0001515	94.64	gold quality
sural nerve	UBERON:0015488	93.86	gold quality
right coronary artery	UBERON:0001625	93.83	gold quality
left coronary artery	UBERON:0001626	92.62	gold quality
endocervix	UBERON:0000458	92.54	gold quality
descending thoracic aorta	UBERON:0002345	92.34	gold quality
colonic epithelium	UBERON:0000397	92.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.84	gold quality
ectocervix	UBERON:0012249	91.59	gold quality
coronary artery	UBERON:0001621	91.32	gold quality
lower esophagus mucosa	UBERON:0035834	91.30	gold quality
esophagus	UBERON:0001043	91.15	gold quality
ganglionic eminence	UBERON:0004023	91.08	gold quality
left uterine tube	UBERON:0001303	90.95	gold quality
cerebellar hemisphere	UBERON:0002245	90.92	gold quality
left testis	UBERON:0004533	90.88	gold quality
transverse colon	UBERON:0001157	90.78	gold quality
cerebellar cortex	UBERON:0002129	90.69	gold quality
ventricular zone	UBERON:0003053	90.64	gold quality
right lobe of liver	UBERON:0001114	90.50	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.33

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, IRF6, MXD1, SPI1

miRNA regulators (miRDB)

58 targeting IGHMBP2, 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-5692A	100.00	74.40	6850
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6809-3P	99.91	71.45	3814
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-7162-3P	99.89	68.16	1682
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-361-3P	99.19	66.45	1381

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 31)

• NMR solution structure of the R3H domain from human Smubp-2 (PMID:12547203)
• association between IgA nephropathy and an SNP located in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2) at chromosome 11q13.2-q13.4 (PMID:15599641)
• IGHMBP2 may not have a role in development of breast cancer in female smokers (PMID:16752224)
• 2 novel heterozygous IGHMBP2 mutations in two cases of SMARD1 were identified: 1061G>A, amino acid substitution G354S, exon 7; 129delC, frameshift mutation, exon 2. (PMID:16964485)
• Juvenile SMARD1 with onset in early childhood can also be caused by mutations of IGHMBP2.5 In accordance with the known phenotypical overlapping between SOD1-associated fALS and SMA, we investigated a selected group of eight sporadic ALS patients. (PMID:18187479)
• Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease. (PMID:18802676)
• SMARD1 phenotype should be considered in cases of atypical spinal muscular atrophy even in the absence of overt diaphragmatic weakness. (PMID:19157874)
• IGHMBP2 is functionally linked to translation, and that mutations in its helicase domain interfere with this function in distal spinal muscular atrophy type 1 patients. (PMID:19158098)
• Variation in IGHMBP2 does not confer significant susceptibility to IgA nephropathy in UK Caucasian or Chinese Han populations. (PMID:20031928)
• Taken together, these observations suggest that the duplicated GGAA motifs are essential for the IGHMBP2 promoter activity and its positive response to TPA in HL-60 cells. (PMID:20441787)
• mutations in the IGHMBP2 gene of patients with more favorable outcomes retained residual enzymatic activity. (PMID:22157136)
• Genetic studies identified 2 mutations in the gene IGHMBP2. These results support the consideration of this entity as a form of sensory-motor rapidly progressive polyneuropathy. (PMID:22791546)
• Results reveal the critical role of the R3H domain in modulation of enzymatic and RNA-binding activities of Ighmbp2. (PMID:22965130)
• report the NMR structure of the Smubp2-R3H in complex with deoxyguanosine 5’-monophosphate (dGMP) mimicking the 5’-end of single-stranded DNA (PMID:22999958)
• The IGHMBP2 gene was not found to be a major causative gene linked to Han Chinese non-5q-spinal muscular atrophy patients. (PMID:24022109)
• 6 novel IGHMBP2 mutations were identified in 5 SMARD1 patietns (PMID:24388491)
• Spinal muscular atrophy with respiratory distress type 1 that is related to mutations in the IGHMBP2 gene, which encodes for the immunoglobulin mu-binding protein. (PMID:25248952)
• Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. (PMID:25439726)
• Mutations in IGHMBP2 were identified in patients presenting with axonal sensorimotor neuropathy. (PMID:25568292)
• IGHMBP2 overexpression may promote invasion and migration of esophageal squamous carcinoma cells through down-regulation of E-cadherin. (PMID:25881701)
• demonstration of 2 additional mutations in the IGHMBP2 gene associated with hereditary motor and sensory neuropathy (PMID:26136520)
• Case report and review of 20 reported spinal muscular atrophy with respiratory distress type I cases that have no respiratory involvement or have late onsets, propose that IGHMBP2 gene mutations are characterized by significant phenotypic heterogeneity (PMID:26922252)
• detected IGHMBP2 mutations in a cohort of Chinese Charcot-Marie-Tooth disease type 2 patients; four mutations, c.1489G > A, c.2356delG, c.2597_2598delAG and c.1061-2A > G, are reported for the first time (PMID:28065684)
• We present the original report of Charcot-Marie-Tooth disease (CMT) type 2S in Japan, and illustrate that recessive IGHMBP2 variants account for ~1.6% of axonal CMT in our cohort. (PMID:28202949)
• We identified a paternally derived splice donor site mutation and a maternally derived missense mutation of IGHMBP2 (PMID:29575095)
• UPF1, a highly processive helicase central to nonsense-mediated mRNA decay (NMD), tightly holds onto NA, allowing long lasting action. Conversely, the structurally similar IGHMBP2 helicase has a short residence time. (PMID:30218034)
• Charcot-Marie-Tooth disease type 2S: identical novel missense mutation of IGHMBP2 gene in two unrelated families. (PMID:34668123)
• Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations. (PMID:35660062)
• Validation of the Pathogenic Effect of IGHMBP2 Gene Mutations Based on Yeast S. cerevisiae Model. (PMID:36077311)
• RNA helicase IGHMBP2 regulates THO complex to ensure cellular mRNA homeostasis. (PMID:38368610)
• IGHMBP2 deletion suppresses translation and activates the integrated stress response. (PMID:38803225)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ighmbp2	ENSDARG00000069274
mus_musculus	Ighmbp2	ENSMUSG00000024831
rattus_norvegicus	Ighmbp2	ENSRNOG00000013456
caenorhabditis_elegans		WBGENE00007329
caenorhabditis_elegans		WBGENE00010989

Paralogs (10): UPF1 (ENSG00000005007), AQR (ENSG00000021776), MOV10L1 (ENSG00000073146), SETX (ENSG00000107290), ZNFX1 (ENSG00000124201), HELZ2 (ENSG00000130589), DNA2 (ENSG00000138346), MOV10 (ENSG00000155363), CT55 (ENSG00000169551), HELZ (ENSG00000198265)

Protein

Protein identifiers

DNA-binding protein SMUBP-2 — P38935 (reviewed: P38935)

Alternative names: ATP-dependent helicase IGHMBP2, Glial factor 1, Immunoglobulin mu-binding protein 2

All UniProt accessions (21): P38935, A0A6Q8PEZ5, A0A6Q8PF00, A0A6Q8PF01, A0A6Q8PF41, A0A6Q8PFK9, A0A6Q8PFN4, A0A6Q8PFP3, A0A6Q8PFZ7, A0A6Q8PGC0, A0A6Q8PGF6, A0A6Q8PGQ2, A0A6Q8PGQ6, A0A6Q8PGT6, A0A6Q8PGX2, A0A6Q8PHG1, A0A6Q8PHH4, A0A6Q8PHR8, A0AAQ5BIJ9, F5GX64, H3BRR1

UniProt curated annotations — full annotation on UniProt →

Function. 5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction. Specific to 5’-phosphorylated single-stranded guanine-rich sequences. May play a role in RNA metabolism, ribosome biogenesis or initiation of translation. May play a role in regulation of transcription. Interacts with tRNA-Tyr.

Subunit / interactions. Homooligomer. Interacts with RUVBL1. Interacts with RUVBL2. Interacts with GTF3C1. Interacts with ABT1. Interacts with ribosomes.

Subcellular location. Nucleus. Cytoplasm. Cell projection. Axon.

Tissue specificity. Expressed in all tissues examined. Expressed in the developing and adult human brain, with highest expression in the cerebellum. Moderately expressed in fibroblasts.

Disease relevance. Neuronopathy, distal hereditary motor, autosomal recessive 1 (HMNR1) [MIM:604320] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, type 2S (CMT2S) [MIM:616155] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The R3H domain recognizes phosphorylated 5’-ends of single-stranded nucleic acids which promotes binding of nucleic acids and stimulates ATPase activity.

Similarity. Belongs to the DNA2/NAM7 helicase family.

RefSeq proteins (1): NP_002171* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000058	Znf_AN1	Domain
IPR001374	R3H_dom	Domain
IPR003593	AAA+_ATPase	Domain
IPR004483	SMUBP-2/Hcs1-like	Family
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR034072	R3H_Smubp-2	Domain
IPR035896	AN1-like_Znf	Homologous_superfamily
IPR036867	R3H_dom_sf	Homologous_superfamily
IPR041677	DNA2/NAM7_AAA_11	Domain
IPR041679	DNA2/NAM7-like_C	Domain
IPR047187	SF1_C_Upf1	Domain
IPR048761	SMUBP-2_HCS1_1B	Domain
IPR050534	Coronavir_polyprotein_1ab	Family

Pfam: PF01424, PF01428, PF13086, PF13087, PF21138

Enzyme classification (BRENDA):

• EC 3.6.4.12 — DNA helicase (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (144 total): sequence variant 41, helix 31, strand 30, binding site 12, turn 10, region of interest 5, sequence conflict 5, compositionally biased region 4, initiator methionine 1, chain 1, domain 1, modified residue 1, zinc finger region 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4B3F	X-RAY DIFFRACTION	2.5
4B3G	X-RAY DIFFRACTION	2.85
1MSZ	SOLUTION NMR
2LRR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P38935-F1	77.87	0.42

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 (12): 214–221; 403; 442; 571; 897; 902; 913; 916; 921; 924; 930; 932

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 225 (showing top): MORF_RAGE, CAR_TNFRSF25, chr11q13, GGAANCGGAANY_UNKNOWN, CAR_MYST2, GOBP_DNA_DAMAGE_RESPONSE, MODULE_157, CAR_MLANA, PEART_HDAC_PROLIFERATION_CLUSTER_DN, MORF_PML, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GOCC_NEURON_PROJECTION, MORF_PDPK1, MORF_IKBKG, MODULE_20

GO Biological Process (0):

GO Molecular Function (24): tRNA binding (GO:0000049), DNA binding (GO:0003677), DNA helicase activity (GO:0003678), single-stranded DNA binding (GO:0003697), RNA binding (GO:0003723), single-stranded RNA binding (GO:0003727), ATP binding (GO:0005524), ATP-dependent activity, acting on DNA (GO:0008094), ATP-dependent activity, acting on RNA (GO:0008186), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), 5’-3’ RNA helicase activity (GO:0032574), double-stranded DNA helicase activity (GO:0036121), identical protein binding (GO:0042802), ribosome binding (GO:0043022), 5’-3’ DNA helicase activity (GO:0043139), general transcription initiation factor binding (GO:0140296), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), RNA helicase activity (GO:0003724), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear body (GO:0016604), axon (GO:0030424), growth cone (GO:0030426), ribonucleoprotein complex (GO:1990904), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
ATP-dependent activity	3
RNA binding	2
nucleic acid binding	2
helicase activity	2
DNA helicase activity	2
ATP-dependent activity, acting on DNA	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ATP hydrolysis activity	1
catalytic activity, acting on DNA	1
transition metal ion binding	1
ribonucleoside triphosphate phosphatase activity	1
RNA helicase activity	1
protein binding	1
ribonucleoprotein complex binding	1
transcription factor binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1
neuron projection	1
site of polarized growth	1
distal axon	1
protein-containing complex	1

Protein interactions and networks

STRING

1180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IGHMBP2	ABT1	Q9ULW3	831
IGHMBP2	GTF3C1	Q12789	752
IGHMBP2	SMN1	Q16637	743
IGHMBP2	GDAP1	Q8TB36	710
IGHMBP2	MN1	Q10571	649
IGHMBP2	ALDH1A1	P00352	632
IGHMBP2	SH3TC2	Q8TF17	631
IGHMBP2	LRSAM1	Q6UWE0	599
IGHMBP2	GARS1	P41250	593
IGHMBP2	BSCL2	Q96G97	591
IGHMBP2	PLEKHG5	O94827	588
IGHMBP2	TTN	Q8WZ42	576
IGHMBP2	SETX	Q7Z333	574
IGHMBP2	RUVBL2	Q9Y230	569
IGHMBP2	DYNC1H1	Q14204	567

IntAct

36 interactions, top by confidence:

A	B	Type	Score
NELFA	NELFE	psi-mi:“MI:0914”(association)	0.900
IGHMBP2	THAP12	psi-mi:“MI:0914”(association)	0.530
NELFE	IGHMBP2	psi-mi:“MI:0914”(association)	0.530
NELFA	IGHMBP2	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
IGHMBP2	PSIP1	psi-mi:“MI:0915”(physical association)	0.400
SMC6	IFT88	psi-mi:“MI:0914”(association)	0.350
HNRNPU		psi-mi:“MI:0914”(association)	0.350
Kif19		psi-mi:“MI:0914”(association)	0.350
SASS6	NFIB	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ORF4a	MPHOSPH10	psi-mi:“MI:0914”(association)	0.350
N	RBM47	psi-mi:“MI:0914”(association)	0.350
FMR1	MYO1C	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
NELFCD	SPTLC2	psi-mi:“MI:0914”(association)	0.350

BioGRID (49): IGHMBP2 (Affinity Capture-MS), IGHMBP2 (Affinity Capture-MS), IGHMBP2 (Affinity Capture-MS), IGHMBP2 (Affinity Capture-MS), IGHMBP2 (Affinity Capture-MS), IGHMBP2 (Two-hybrid), IGHMBP2 (Affinity Capture-MS), TUBA8 (Affinity Capture-MS), IGHMBP2 (Affinity Capture-MS), WDR89 (Affinity Capture-MS), NLE1 (Affinity Capture-MS), PRKRIR (Affinity Capture-MS), WDR12 (Affinity Capture-MS), GRSF1 (Affinity Capture-MS), RPL5 (Affinity Capture-MS)

ESM2 similar proteins: A0JNK3, A2RT60, A4IHA1, A6YFB5, A9JRB3, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D3ZA76, D3ZKF5, E1BJW1, F1N152, F4J3G5, O22609, O23614, O43464, P14543, P38935, P73940, P83105, P83110, Q14689, Q14703, Q297U2, Q3U213, Q5SNQ7, Q5XIL0, Q6GMI0, Q852K0, Q8BMS2, Q8IUL8, Q8IZJ1, Q91XF4

Diamond homologs: A0A1P8ASY1, A2AKX3, D3ZG52, E1BMP7, E9QAM5, O94387, P30771, P38859, P38935, P51530, Q5ZKG3, Q6ZQJ5, Q7Z333, Q8QHA5, Q92355, Q92900, Q98TR3, Q9EPU0, Q9HEH1, Q9URU2, B6SFA4, F1RCY6, O76512, O94247, P23249, P32644, P40694, Q00416, Q09449, Q09820, Q0V8H6, Q0VGT4, Q1LXK4, Q54I89, Q57568, Q60560, Q86AS0, Q86YA3, Q8GYD9, Q8R151

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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
Infectious disease	5	5.9×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1507 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	101
Likely pathogenic	43
Uncertain significance	563
Likely benign	539
Benign	69

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070991	NM_002180.3(IGHMBP2):c.763_767del (p.Leu255fs)	Pathogenic
1073962	NC_000011.9:g.(?68671411)(68707209_?)del	Pathogenic
1075876	NM_002180.3(IGHMBP2):c.373C>T (p.Gln125Ter)	Pathogenic
1175183	NM_002180.3(IGHMBP2):c.1061-2A>G	Pathogenic
1188696	NM_002180.3(IGHMBP2):c.2039del (p.Gln680fs)	Pathogenic
1299363	NM_002180.3(IGHMBP2):c.2796del (p.Cys932fs)	Pathogenic
1371633	NM_002180.3(IGHMBP2):c.696_700del (p.Lys233fs)	Pathogenic
1379465	NM_002180.3(IGHMBP2):c.1305_1350del (p.Arg436fs)	Pathogenic
1393140	NM_002180.3(IGHMBP2):c.467del (p.Lys156fs)	Pathogenic
1426154	NM_002180.3(IGHMBP2):c.1477A>G (p.Thr493Ala)	Pathogenic
1451211	NM_002180.3(IGHMBP2):c.211C>T (p.Arg71Ter)	Pathogenic
162194	NM_002180.3(IGHMBP2):c.138T>A (p.Cys46Ter)	Pathogenic
162197	NM_002180.3(IGHMBP2):c.1118T>G (p.Val373Gly)	Pathogenic
1945190	NM_002180.3(IGHMBP2):c.891del (p.Lys298fs)	Pathogenic
2033010	NM_002180.3(IGHMBP2):c.317_318insA (p.Thr107fs)	Pathogenic
204304	NM_002180.3(IGHMBP2):c.2784+1G>T	Pathogenic
2130513	NM_002180.3(IGHMBP2):c.1919_1920dup (p.Glu641fs)	Pathogenic
2157555	NM_002180.3(IGHMBP2):c.1969dup (p.Gln657fs)	Pathogenic
2424363	NC_000011.9:g.(?68671421)(68679091_?)del	Pathogenic
2424364	NC_000011.9:g.(?68673517)(68682511_?)del	Pathogenic
2424365	NC_000011.9:g.(?68682271)(68682511_?)del	Pathogenic
242498	NM_002180.3(IGHMBP2):c.660A>C (p.Lys220Asn)	Pathogenic
242499	NM_002180.3(IGHMBP2):c.92G>A (p.Trp31Ter)	Pathogenic
243079	NM_002180.3(IGHMBP2):c.1346del (p.Met449fs)	Pathogenic
2444085	NM_002180.3(IGHMBP2):c.2599A>T (p.Lys867Ter)	Pathogenic
245626	NM_002180.3(IGHMBP2):c.1060+2T>C	Pathogenic
245627	NM_002180.3(IGHMBP2):c.1082T>C (p.Leu361Pro)	Pathogenic
2498526	NM_002180.3(IGHMBP2):c.1917del (p.Phe640fs)	Pathogenic
282112	NM_002180.3(IGHMBP2):c.2197_2203delinsCA (p.Ile733fs)	Pathogenic
282335	NM_002180.3(IGHMBP2):c.2560C>T (p.Gln854Ter)	Pathogenic

SpliceAI

2461 predictions. Top by Δscore:

Variant	Effect	Δscore
11:68904037:AG:A	donor_loss	1.0000
11:68904038:GG:G	donor_loss	1.0000
11:68904039:G:GG	donor_gain	1.0000
11:68906192:GCGA:G	donor_gain	1.0000
11:68906221:G:GG	donor_gain	1.0000
11:68908139:TTGCA:T	acceptor_loss	1.0000
11:68908140:TGCA:T	acceptor_loss	1.0000
11:68908142:CAGGT:C	acceptor_loss	1.0000
11:68908143:A:AG	acceptor_gain	1.0000
11:68908143:AG:A	acceptor_gain	1.0000
11:68908143:AGGT:A	acceptor_gain	1.0000
11:68908143:AGGTG:A	acceptor_loss	1.0000
11:68908144:G:GA	acceptor_gain	1.0000
11:68908144:GG:G	acceptor_gain	1.0000
11:68908144:GGT:G	acceptor_gain	1.0000
11:68908144:GGTG:G	acceptor_gain	1.0000
11:68908144:GGTGA:G	acceptor_gain	1.0000
11:68908335:AAA:A	donor_gain	1.0000
11:68908336:AA:A	donor_gain	1.0000
11:68908337:AGTA:A	donor_loss	1.0000
11:68908338:G:GG	donor_gain	1.0000
11:68908339:TAAGT:T	donor_loss	1.0000
11:68908632:G:GG	donor_gain	1.0000
11:68911435:CACA:C	acceptor_loss	1.0000
11:68911436:ACAG:A	acceptor_loss	1.0000
11:68911437:CAGAC:C	acceptor_loss	1.0000
11:68911438:A:AG	acceptor_gain	1.0000
11:68911439:G:GG	acceptor_gain	1.0000
11:68911439:GAC:G	acceptor_gain	1.0000
11:68911439:GACC:G	acceptor_gain	1.0000

AlphaMissense

6440 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:68936248:T:C	F590L	0.999
11:68936250:T:A	F590L	0.999
11:68936250:T:G	F590L	0.999
11:68935357:T:A	V564D	0.997
11:68936297:G:C	R606P	0.996
11:68911551:A:T	K220I	0.995
11:68935405:T:A	V580D	0.995
11:68935408:G:C	R581T	0.995
11:68936249:T:C	F590S	0.995
11:68936291:C:A	A604D	0.995
11:68914836:C:A	A242D	0.994
11:68914851:C:A	A247D	0.994
11:68929249:A:T	E376V	0.994
11:68929278:T:A	W386R	0.993
11:68929278:T:C	W386R	0.993
11:68936249:T:G	F590C	0.993
11:68936765:C:A	A762D	0.993
11:68914856:G:C	D249H	0.992
11:68929260:G:C	A380P	0.992
11:68933909:C:A	N511K	0.992
11:68933909:C:G	N511K	0.992
11:68934533:C:A	A536D	0.992
11:68935371:G:C	G569R	0.992
11:68935409:A:C	R581S	0.992
11:68935409:A:T	R581S	0.992
11:68936279:C:A	A600D	0.992
11:68904019:G:C	A23P	0.991
11:68914901:C:A	R264S	0.991
11:68933324:A:C	S421R	0.991
11:68933326:C:A	S421R	0.991

dbSNP variants (sampled 300 via entrez): RS1000078980 (11:68906004 T>C), RS1000091588 (11:68935374 C>T), RS1000159945 (11:68932560 T>A,C), RS1000309507 (11:68902222 G>A), RS1000316810 (11:68939849 C>A,T), RS1000385785 (11:68930355 G>A), RS1000458045 (11:68940042 C>T), RS1000470474 (11:68934689 T>A), RS1000559810 (11:68919521 A>G,T), RS1000560736 (11:68905739 CG>C), RS1000669795 (11:68926016 G>C), RS1000671882 (11:68916404 A>C), RS1000821276 (11:68934905 C>G), RS1000868217 (11:68938862 A>G), RS1000994208 (11:68910656 G>A)

Disease associations

OMIM: gene MIM:600502 | disease phenotypes: MIM:604320, MIM:616155, MIM:118220, MIM:182960, MIM:145290, MIM:613376, MIM:253300

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive distal spinal muscular atrophy 1	Definitive	Autosomal recessive
Charcot-Marie-Tooth disease axonal type 2S	Definitive	Autosomal recessive
hereditary peripheral neuropathy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary peripheral neuropathy	Definitive	AR

Mondo (16): autosomal recessive distal spinal muscular atrophy 1 (MONDO:0011436), Charcot-Marie-Tooth disease axonal type 2S (MONDO:0014511), Charcot-Marie-Tooth disease (MONDO:0015626), peripheral neuropathy (MONDO:0005244), distal hereditary motor neuropathy (MONDO:0018894), neurodevelopmental disorder (MONDO:0700092), neuronopathy, distal hereditary motor, autosomal dominant (MONDO:0015362), ptosis (MONDO:0000728), hyperreflexia (MONDO:0007774), neuronopathy, distal hereditary motor, type 2C (MONDO:0013243), Charcot-Marie-Tooth disease type 1 (MONDO:0019011), neuronopathy, distal hereditary motor, autosomal dominant 1 (MONDO:0008451), spinal muscular atrophy (MONDO:0001516), Charcot-Marie-Tooth disease type 4 (MONDO:0018995), autosomal dominant intermediate Charcot-Marie-Tooth disease (MONDO:0019548)

Orphanet (10): Charcot-Marie-Tooth disease type 2S (Orphanet:443073), Spinal muscular atrophy with respiratory distress type 1 (Orphanet:98920), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Distal hereditary motor neuropathy (Orphanet:53739), Autosomal dominant distal hereditary motor neuropathy (Orphanet:140465), Distal hereditary motor neuropathy type 2 (Orphanet:139525), Charcot-Marie-Tooth disease type 1 (Orphanet:65753), Distal hereditary motor neuropathy type 1 (Orphanet:139518), Charcot-Marie-Tooth disease type 4 (Orphanet:64749), Autosomal dominant intermediate Charcot-Marie-Tooth disease (Orphanet:90114)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000762	Decreased nerve conduction velocity
HP:0000764	Peripheral axonal degeneration
HP:0000975	Hyperhidrosis
HP:0001265	Hyporeflexia
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001558	Decreased fetal movement
HP:0001612	Weak cry
HP:0001622	Premature birth
HP:0001762	Talipes equinovarus
HP:0002019	Constipation
HP:0002398	Degeneration of anterior horn cells
HP:0002460	Distal muscle weakness
HP:0002522	Areflexia of lower limbs
HP:0002650	Scoliosis
HP:0002789	Tachypnea
HP:0002878	Respiratory failure
HP:0002936	Distal sensory impairment
HP:0003376	Steppage gait
HP:0003445	EMG: neuropathic changes
HP:0003484	Upper limb muscle weakness
HP:0003577	Congenital onset
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0003690	Limb muscle weakness

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006288_423	Heel bone mineral density	3.000000e-08
GCST006288_44	Heel bone mineral density	5.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D001763	Blepharoptosis	C11.338.204
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D009134	Muscular Atrophy, Spinal	C10.228.854.468; C10.574.562.500; C10.668.467.500
D065886	Neurodevelopmental Disorders	F03.625
D012021	Reflex, Abnormal	C10.597.704; C23.888.592.717; E01.370.376.550.650.655; E01.370.600.550.650.655; G11.561.731.587
C566675	Neuronopathy, Distal Hereditary Motor, Type I (supp.)
C536880	Spinal muscular atrophy with respiratory distress 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Smoke	decreases expression, increases abundance, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	increases expression, affects expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	increases expression	1
myristicin	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cupric chloride	increases expression	1
CGP 52608	increases reaction, affects binding	1
deguelin	decreases expression	1
abrine	increases expression	1
pyrachlostrobin	decreases expression	1
bisphenol S	decreases methylation	1
picoxystrobin	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Methotrexate	decreases expression	1
Paraquat	increases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation, increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy