MLXIP

Summary

MLXIP (MLX interacting protein, HGNC:17055) is a protein-coding gene on chromosome 12q21.31, encoding MLX-interacting protein (Q9HAP2). Binds DNA as a heterodimer with MLX and activates transcription.

This gene encodes a protein that functions as part of a heterodimer to activate transcription. The encoded protein forms a heterodimer with Max-like protein X (MLX) and is involved in the regulation of genes in response to cellular glucose levels.

Source: NCBI Gene 22877 — RefSeq curated summary.

At a glance

• GWAS associations: 31 (top 4% of genes corpus-wide)
• Clinical variants (ClinVar): 56 total — 1 pathogenic
• GTEx eGene: eQTL in 21 tissues, sQTL in 35 (q < 0.05)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.46 (moderately constrained)
• MANE Select transcript: NM_014938
• Notable: 56 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17055
Approved symbol	MLXIP
Name	MLX interacting protein
Location	12q21.31
Locus type	gene with protein product
Status	Approved
Aliases	MONDOA, KIAA0867, MIR, bHLHe36
Ensembl gene	ENSG00000175727
Ensembl biotype	protein_coding
OMIM	608090
Entrez	22877

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000319080

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 3, TSL 5: 1

ENST00000319080, ENST00000366272, ENST00000535430, ENST00000535876, ENST00000535996, ENST00000538061, ENST00000538698, ENST00000539861, ENST00000541750, ENST00000542417, ENST00000890511, ENST00000890512, ENST00000945225, ENST00000945226, ENST00000945227, ENST00000945228, ENST00000945229, ENST00000945230, ENST00001118768, ENST00001139651

RefSeq mRNA: 1 — MANE Select: NM_014938 NM_014938

CCDS: CCDS73540

Canonical transcript exons

ENST00000319080 — 17 exons

Exon	Start	End
ENSE00001278864	122140954	122141083
ENSE00001278872	122138815	122138938
ENSE00001278878	122138424	122138551
ENSE00001278929	122127883	122127968
ENSE00001278951	122138194	122138295
ENSE00001278956	122137469	122137590
ENSE00001278960	122135489	122135666
ENSE00001279017	122133348	122133987
ENSE00001472589	122078756	122079266
ENSE00001796587	122127256	122127362
ENSE00003467741	122130844	122130933
ENSE00003500106	122129137	122129226
ENSE00003513193	122132292	122132383
ENSE00003559488	122129941	122130112
ENSE00003629977	122129588	122129629
ENSE00003663423	122135224	122135345
ENSE00004795279	122141691	122147344

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 98.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.2482 / max 249.6083, expressed in 1797 samples.

Highest expression (Bgee): ileal mucosa, tibialis anterior, gastrocnemius, muscle layer of sigmoid colon, muscle of leg.

Genetic regulation across tissues (GTEx eQTL / sQTL)

MLXIP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 21 tissues and its splicing (sQTL) in 35 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 56 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	3.1e-109	+0.82	12:122134850:C:T
Thyroid	sqtl	3.1e-51	-0.83	12:122142295:G:A
Whole Blood	sqtl	5.5e-37	-0.65	12:122137660:CT:C
Colon Transverse	eqtl	1.7e-30	+0.41	12:122097852:T:C
Esophagus Muscularis	sqtl	5.1e-27	+0.50	12:122086876:A:G
Artery Tibial	sqtl	9.0e-26	+0.54	12:122086876:A:G
Testis	sqtl	2.2e-25	-0.84	12:122131552:C:T
Testis	eqtl	1.3e-23	+0.98	12:122080337:A:G
Lung	sqtl	2.6e-22	-0.67	12:122145462:G:T
Cells Cultured fibroblasts	sqtl	6.0e-20	-0.56	12:122145462:G:T
Colon Sigmoid	sqtl	1.6e-19	-0.70	12:122129052:A:G
Adipose Subcutaneous	sqtl	3.0e-19	-0.44	12:122130968:C:G
Pancreas	sqtl	3.9e-14	+0.80	12:122145738:G:A
Breast Mammary Tissue	sqtl	7.3e-14	+0.61	12:122128993:T:C
Cells Cultured fibroblasts	eqtl	7.7e-14	+0.19	12:122129052:A:G
Artery Aorta	sqtl	3.6e-13	+0.53	12:122086876:A:G
Colon Transverse	sqtl	5.9e-13	-0.74	12:122125035:G:A
Esophagus Mucosa	sqtl	6.2e-13	+0.42	12:122115249:C:T
Adipose Visceral Omentum	sqtl	2.4e-12	-0.57	12:122137660:CT:C
Brain Cerebellum	sqtl	8.0e-12	-0.81	12:122138453:T:C

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
128509	15.7013	1788
128508	2.2008	1310
128510	1.0925	717
206940	0.1357	42
128511	0.1179	40

Top tissues by expression

showing 100 of 252 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	98.55	gold quality
tibialis anterior	UBERON:0001385	97.96	gold quality
gastrocnemius	UBERON:0001388	97.08	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.42	gold quality
muscle of leg	UBERON:0001383	96.25	gold quality
pancreatic ductal cell	CL:0002079	96.02	gold quality
parotid gland	UBERON:0001831	95.86	gold quality
colonic epithelium	UBERON:0000397	95.84	gold quality
transverse colon	UBERON:0001157	95.75	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.60	gold quality
colon	UBERON:0001155	95.31	gold quality
large intestine	UBERON:0000059	95.06	gold quality
quadriceps femoris	UBERON:0001377	94.97	gold quality
mucosa of stomach	UBERON:0001199	94.86	gold quality
body of pancreas	UBERON:0001150	94.77	gold quality
vastus lateralis	UBERON:0001379	94.56	gold quality
skeletal muscle tissue	UBERON:0001134	94.45	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.37	gold quality
rectum	UBERON:0001052	94.30	gold quality
colonic mucosa	UBERON:0000317	94.29	gold quality
intestine	UBERON:0000160	94.09	gold quality
muscle tissue	UBERON:0002385	93.98	gold quality
deltoid	UBERON:0001476	93.97	gold quality
left ovary	UBERON:0002119	93.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.90	gold quality
right lobe of thyroid gland	UBERON:0001119	93.83	gold quality
right ovary	UBERON:0002118	93.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.68	gold quality
lower esophagus	UBERON:0013473	93.65	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.47	gold quality
left lobe of thyroid gland	UBERON:0001120	93.34	gold quality
thyroid gland	UBERON:0002046	93.20	gold quality
tendon of biceps brachii	UBERON:0008188	93.20	gold quality
vermiform appendix	UBERON:0001154	92.94	gold quality
pancreas	UBERON:0001264	92.88	gold quality
body of stomach	UBERON:0001161	92.85	gold quality
smooth muscle tissue	UBERON:0001135	92.76	gold quality
bone marrow cell	CL:0002092	92.72	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.70	gold quality
oviduct epithelium	UBERON:0004804	92.49	gold quality
right uterine tube	UBERON:0001302	92.43	gold quality
left uterine tube	UBERON:0001303	92.35	gold quality
small intestine	UBERON:0002108	92.34	gold quality
biceps brachii	UBERON:0001507	92.18	gold quality
ovary	UBERON:0000992	92.17	gold quality
body of uterus	UBERON:0009853	92.17	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.81	gold quality
stomach	UBERON:0000945	91.70	gold quality
popliteal artery	UBERON:0002250	91.56	gold quality
tibial artery	UBERON:0007610	91.55	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.49	gold quality
caecum	UBERON:0001153	91.44	gold quality
fundus of stomach	UBERON:0001160	91.37	gold quality
mucosa of transverse colon	UBERON:0004991	91.36	gold quality
right coronary artery	UBERON:0001625	91.35	gold quality
fallopian tube	UBERON:0003889	91.21	gold quality
urinary bladder	UBERON:0001255	91.17	gold quality
upper lobe of left lung	UBERON:0008952	90.76	gold quality
left adrenal gland cortex	UBERON:0035825	90.67	gold quality
metanephros cortex	UBERON:0010533	90.64	gold quality
left adrenal gland	UBERON:0001234	90.63	gold quality
gall bladder	UBERON:0002110	90.63	gold quality
left coronary artery	UBERON:0001626	90.54	gold quality
right adrenal gland	UBERON:0001233	90.53	gold quality
blood	UBERON:0000178	90.48	gold quality
upper lobe of lung	UBERON:0008948	90.26	gold quality
omental fat pad	UBERON:0010414	90.14	gold quality
peritoneum	UBERON:0002358	90.10	gold quality
aorta	UBERON:0000947	90.05	gold quality
coronary artery	UBERON:0001621	90.03	gold quality
right adrenal gland cortex	UBERON:0035827	89.93	gold quality
adrenal gland	UBERON:0002369	89.86	gold quality
spleen	UBERON:0002106	89.84	gold quality
stromal cell of endometrium	CL:0002255	89.81	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.79	gold quality
adrenal cortex	UBERON:0001235	89.76	gold quality
myometrium	UBERON:0001296	89.76	gold quality
apex of heart	UBERON:0002098	89.65	gold quality
islet of Langerhans	UBERON:0000006	89.48	gold quality
saliva-secreting gland	UBERON:0001044	89.34	gold quality
left ventricle myocardium	UBERON:0006566	89.31	gold quality
saphenous vein	UBERON:0007318	89.24	gold quality
esophagus	UBERON:0001043	89.22	gold quality
right atrium auricular region	UBERON:0006631	88.91	gold quality
prostate gland	UBERON:0002367	88.88	gold quality
epithelial cell of pancreas	CL:0000083	88.73	gold quality
cardiac atrium	UBERON:0002081	88.71	gold quality
sural nerve	UBERON:0015488	88.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.61	gold quality
endocervix	UBERON:0000458	88.59	gold quality
cerebellar hemisphere	UBERON:0002245	88.45	gold quality
descending thoracic aorta	UBERON:0002345	88.41	gold quality
minor salivary gland	UBERON:0001830	88.40	gold quality
granulocyte	CL:0000094	88.32	gold quality
cerebellar cortex	UBERON:0002129	88.26	gold quality
thoracic aorta	UBERON:0001515	88.25	gold quality
ascending aorta	UBERON:0001496	88.23	gold quality
monocyte	CL:0000576	88.22	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.22	gold quality
right lobe of liver	UBERON:0001114	88.15	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	61.95
E-HCAD-4	yes	46.85
E-MTAB-9067	yes	17.70
E-GEOD-125970	yes	16.73
E-GEOD-137537	yes	6.27
E-ANND-3	yes	5.99
E-CURD-122	yes	5.68
E-MTAB-4850	no	95.90

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	107.2	high
Colon	tissue	43.4	high
Rectum	tissue	41.5	high
Tongue	tissue	39.4
Pancreas	tissue	34.6	medium
Choroid plexus	tissue	33.8
Bone marrow	tissue	33.8	medium
Small intestine	tissue	31.5	high
Nucleus accumbens	tissue	30.5
Salivary gland	tissue	30.1	medium
Smooth muscle	tissue	30.1	medium
Ovary	tissue	28.9	low
Appendix	tissue	27.9	high
Locus coeruleus	tissue	27.3
Hippocampus	tissue	27.2	medium
Postcentral gyrus	tissue	25.8
Duodenum	tissue	25.1	high
Fallopian tube	tissue	24.4	medium
Epididymis	tissue	23.8	medium
Skin 1	tissue	23.7	medium
Pituitary gland	tissue	20.5
Thyroid gland	tissue	20.3	high
Adipose tissue	tissue	20.2	medium
Spleen	tissue	20.0	medium
Gallbladder	tissue	20.0	high
Endometrium 1	tissue	19.5	medium
Stomach 1	tissue	19.1	medium
Seminal vesicle	tissue	17.8	medium
Vagina	tissue	16.4	medium
Lung	tissue	16.3	medium
Adrenal gland	tissue	16.1	high
Lymph node	tissue	16.0	medium
Urinary bladder	tissue	16.0	medium
Esophagus	tissue	14.5	high
Prostate	tissue	14.0	medium
Heart muscle	tissue	13.8	high
Thymus	tissue	13.2
Tonsil	tissue	12.7	medium
Parathyroid gland	tissue	12.1	medium
Placenta	tissue	11.7	medium
Retina	tissue	10.2
Testis	tissue	9.7	medium
Breast	tissue	9.6	medium
Cerebellum	tissue	8.9	medium
Cervix	tissue	8.3	medium
Hippocampal formation	tissue	7.8
Hypothalamus	tissue	6.8
Substantia nigra	tissue	6.8
Kidney	tissue	6.8	medium
Spinal cord	tissue	6.8
Superior colliculi	tissue	6.5
Septum	tissue	6.5
Cerebral cortex	tissue	6.4	high
Corpus callosum	tissue	6.4
Insular cortex	tissue	6.4
Ventral forebrain	tissue	6.3
Basal ganglia	tissue	6.2	medium
Medulla oblongata	tissue	6.2
Periaqueductal gray	tissue	6.2
Amygdala	tissue	6.1

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Flocculonodular lobe (40.9), Temporal white matter (39.2), Piriform cortex (38.8), Parieto-temporal junction (white matter) (36.8), Vermis (36.7).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets:

Target	Regulation
KIT
LDHA	Activation
MIR223
MLH1
PFKFB3
TXNIP	Unknown

miRNA regulators (miRDB)

Targeting MLXIP by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 235 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4514	99.99	67.10	1870

Functional genomics

gnomAD constraint: pLI 0.999, LOEUF 0.461, missense Z 2.56 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000319080 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:122,078,854–122,079,065	129 / 104.2	1.24	no
12:122,079,066–122,129,949	127 / 239.0	0.53	no
12:122,129,950–122,141,809	746 / 897.0	0.83	no

Literature-anchored findings (GeneRIF, showing 21)

• Data show that for both MondoA and Mlx, the C-terminal domain CRM-1 has cytoplasmic localization activity that is required by the protein monomers to accumulate in the cytoplasm. (PMID:12446771)
• Endogenous MondoA and Mlx associate with mitochondria in primary skeletal muscle. (PMID:16782875)
• These studies suggest a key role for MondoA:Mlx complexes in the adaptive transcriptional response to changes in extracellular glucose concentration and peripheral glucose uptake. (PMID:18458340)
• Data suggest that glutamine-dependent mitochondrial anapleurosis dictates glucose uptake and aerobic glycolysis by blocking MondoA:Mlx-dependent transcriptional activation of TXNIP. (PMID:19706488)
• Glucose is required at two additional steps to stimulate the transcription activation function of MondoA-Mlx complexes. (PMID:20385767)
• Induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. (PMID:20844768)
• the MondoA-TXNIP regulatory circuit has a role in the hexose transport curb, although other redundant pathways also contribute (PMID:21908621)
• An important contribution of MondoA to leukemia aggressiveness, which makes MondoA a potential candidate for targeted treatment of acute lymphoblastic leukemia. (PMID:22748921)
• Suppression of Txnip by lipopolysaccharide is accompanied by a decrease of the glucose sensing transcription factor MondoA in the nuclei. (PMID:23520550)
• These results suggest that C771G polymorphism of MLXIPL gene is associated with coronary stenosis and its severity. (PMID:25179879)
• regulatory relationship between mTOR and the MondoA-TXNIP axis that we propose contributes to glucose homeostasis (PMID:25332233)
• Knockdown of MondoA, or its dimerization partner Mlx, blocks Myc-induced reprogramming of multiple metabolic pathways, resulting in apoptosis (PMID:25640402)
• Evaluation of the conservation of ChREBP and MondoA sequences demonstrate that MondoA is better conserved and potentially mediates more ancient function in glucose metabolism. (PMID:26910886)
• MondoA-directed programs have a key role in the coordinated control of myocyte lipid balance and insulin signaling (PMID:27500491)
• Data (including data from studies in knockout mice) suggest that MONDOA shuttles to nucleus of pancreatic beta-cells where it is required for induction of glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP). (PMID:29282201)
• In response to acidosis, MondoA shows preferential binding to just two targets, TXNIP and its paralog ARRDC4. Because these transcriptional targets are suppressors of glucose uptake, the authors propose that MondoA is critical for restoring metabolic homeostasis in response to high energy charge. (PMID:30717828)
• MondoA drives muscle lipid accumulation and insulin resistance. (PMID:31287806)
• TXNIP induced by MondoA, rather than ChREBP, suppresses cervical cancer cell proliferation, migration and invasion. (PMID:31782782)
• MondoA-Thioredoxin-Interacting Protein Axis Maintains Regulatory T-Cell Identity and Function in Colorectal Cancer Microenvironment. (PMID:33901495)
• MondoA drives malignancy in B-ALL through enhanced adaptation to metabolic stress. (PMID:33908607)
• Genetic polymorphisms of LMX1B and MLXIP are associated with hip osteoarthritis in the Chinese population. (PMID:39263770)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mlxip	ENSDARG00000059474
mus_musculus	Mlxip	ENSMUSG00000038342
rattus_norvegicus	Mlxip	ENSRNOG00000001255
drosophila_melanogaster	Mondo	FBGN0032940
caenorhabditis_elegans		WBGENE00003378

Paralogs (3): MLXIPL (ENSG00000009950), TFAP4 (ENSG00000090447), MLX (ENSG00000108788)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2141183) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 6 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal muscle physiology	1
decreased respiratory quotient	1
enhanced exercise endurance	1
increased circulating lactate level	1
increased fatty acid oxidation	1
increased circulating alanine level	1

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CFAP251	protein-coding	144406
LRRC43	protein-coding	254050
IL31	protein-coding	386653
BCL7A	protein-coding	605
LINC02985	ncRNA	100506691
DIABLO	protein-coding	56616
B3GNT4	protein-coding	79369
PSMD9	protein-coding	5715
VPS33A	protein-coding	65082
CLIP1	protein-coding	6249

Protein

Protein identifiers

MLX-interacting protein — Q9HAP2 (reviewed: Q9HAP2)

Alternative names: Class E basic helix-loop-helix protein 36, Transcriptional activator MondoA

All UniProt accessions (4): Q9HAP2, F5H0V4, F5H321, H0YGR9

UniProt curated annotations — full annotation on UniProt →

Function. Binds DNA as a heterodimer with MLX and activates transcription. Binds to the canonical E box sequence 5’-CACGTG-3’. Plays a role in transcriptional activation of glycolytic target genes. Involved in glucose-responsive gene regulation.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a homodimer or a heterodimer with MLX.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion outer membrane.

Tissue specificity. Widely expressed in adult tissues. Most abundant in skeletal muscle.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9HAP2-1	1	yes
Q9HAP2-2	2
Q9HAP2-3	3
Q9HAP2-4	4
Q9HAP2-5	5

RefSeq proteins (1): NP_055753* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR052207	Max-like/E-box_TFs	Family

Pfam: PF00010

UniProt features (28 total): region of interest 7, modified residue 6, splice variant 6, compositionally biased region 4, sequence variant 2, initiator methionine 1, chain 1, domain 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAP2-F1	54.60	0.15

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Basic domains

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

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

Post-translational modifications (6)

Type	Positions
N-acetylalanine	2
Phosphoserine	9, 27, 33, 39, 669

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 194 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_NTN1_TARGETS_DN, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_DN, GOCC_MITOCHONDRIAL_ENVELOPE, BENPORATH_ES_CORE_NINE_CORRELATED, GOBP_CARBOHYDRATE_HOMEOSTASIS, HASLINGER_B_CLL_WITH_CHROMOSOME_12_TRISOMY, DANG_BOUND_BY_MYC, MARIADASON_RESPONSE_TO_BUTYRATE_SULINDAC_6, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, OSMAN_BLADDER_CANCER_DN, SENESE_HDAC3_TARGETS_DN, GOCC_RNA_POLYMERASE_II_TRANSCRIPTION_REGULATOR_COMPLEX, GOCC_TRANSCRIPTION_REGULATOR_COMPLEX

GO Biological Process (4): DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), glucose homeostasis (GO:0042593), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (6): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), protein dimerization activity (GO:0046983), DNA binding (GO:0003677)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), mitochondrial outer membrane (GO:0005741), cytoplasm (GO:0005737)

GO top-level categories

23 GO namespaces:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
cellular anatomical structure	2
gene expression	1
RNA biosynthetic process	1
regulation of DNA-templated transcription	1
carbohydrate homeostasis	1
positive regulation of DNA-templated transcription	1
transcription cis-regulatory region binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
protein binding	1
nucleic acid binding	1
chromosome	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
positive regulation of transcription by RNA polymerase II	BP	direct assay
DNA-binding transcription activator activity, RNA polymerase II-specific	MF	direct assay
RNA polymerase II transcription regulatory region sequence-specific DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 530 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MLXIP	MXD4	Q14582	888
MLXIP	HSD17B1	P14061	721
MLXIP	XPO1	O14980	702
MLXIP	TXNIP	Q9H3M7	678
MLXIP	MXD1	Q05195	651
MLXIP	MXD3	Q9BW11	634
MLXIP	ARRDC4	Q8NCT1	627
MLXIP	MXI1	P50539	590
MLXIP	SIN3A	Q96ST3	586
MLXIP	MNT	Q99583	536
MLXIP	MAX	P25912	445
MLXIP	MYC	P01106	423
MLXIP	FASN	P49327	390
MLXIP	MLX	Q9UH92	385
MLXIP	TXN	P10599	384

IntAct

Human interaction partners of MLXIP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
H2BC9	physical association	0.400	1
RAN	physical association	0.400	1

BioGRID (40 interactions; top human partners by supporting records): MLX (Reconstituted Complex; 8 records), PRMT1 (Affinity Capture-MS; 4 records), YWHAB (Affinity Capture-Western; 4 records), MTOR (Affinity Capture-Western; 3 records), PNKD (Affinity Capture-MS; 2 records), YWHAE (Affinity Capture-MS; 2 records), YWHAG (Affinity Capture-MS; 2 records), BICD1 (Proximity Label-MS), HIST1H2BH (Cross-Linking-MS (XL-MS)), HIST1H4A (Affinity Capture-MS), NUDT21 (Affinity Capture-RNA), PARP16 (Proximity Label-MS), RAN (Cross-Linking-MS (XL-MS)), RIT1 (Negative Genetic), TNFAIP2 (Affinity Capture-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
MLXIP	“form complex”	“MLXIP-MLX transcription factor complex”	binding

Disease & clinical

Genetic variants

Variant evidence for MLXIP: 56 ClinVar records (1 pathogenic / likely pathogenic); 31 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	33
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1527743	GRCh37/hg19 12q24.31(chr12:121882818-122666131)x1	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore MLXIP’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 2,032):

Position(s)	Effect	Δscore	Sites
12:122127254–122127255	acceptor_loss	1.0000	6
12:122127881–122127882	acceptor_loss	1.0000	4
12:122129135–122129136	acceptor_loss	1.0000	6
12:122129190	donor_gain	1.0000
12:122129227	donor_gain	1.0000
12:122129228	donor_loss	1.0000	2
12:122129927	acceptor_gain	1.0000
12:122129939–122129940	acceptor_loss	1.0000	5
12:122130113–122130114	donor_loss	1.0000	5
12:122132384–122132385	donor_loss	1.0000	5

AlphaMissense

1,483 missense substitutions predicted likely pathogenic (of 6,023 scored), across 348 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M83	9	0.988	0.999
H81	8	0.997	0.999
N163	8	0.996	1.000
H78	8	0.995	0.999
F82	8	0.995	1.000
D123	8	0.994	0.998
N164	8	0.994	1.000
D310	8	0.991	0.998
S79	8	0.987	0.999
F149	8	0.987	0.999
F185	8	0.986	0.999
D158	8	0.980	0.998
F130	8	0.974	0.995
H88	8	0.973	0.992
F99	8	0.963	0.996
F286	8	0.957	0.990
D283	8	0.945	0.986
F112	8	0.939	0.997
D98	8	0.931	0.981
N308	8	0.922	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000392

Disease associations

OMIM: gene MIM:608090 | disease phenotypes:

GWAS associations

showing 30 of 31 associations:

Study	Trait	p-value
GCST90011898_58	Alanine aminotransferase levels	5e-25
GCST008972_68	Urate levels	3e-21
GCST006627_2	Diastolic blood pressure	1e-18
GCST90020028_1651	Hip circumference adjusted for BMI	3e-16
GCST90020025_1083	Waist-to-hip ratio adjusted for BMI	6e-16
GCST90020027_301	Waist-hip index	4e-15
GCST90002392_572	Mean corpuscular volume	2e-14
GCST90020025_1086	Waist-to-hip ratio adjusted for BMI	5e-14
GCST90020027_304	Waist-hip index	1e-13
GCST90020025_1084	Waist-to-hip ratio adjusted for BMI	7e-13
GCST90020027_302	Waist-hip index	1e-12
GCST90002403_483	Red blood cell count	2e-12
GCST012338_30	Gout	3e-12
GCST90000025_320	Appendicular lean mass	9e-11
GCST008129_10	Body mass index	3e-10
GCST90002396_67	Mean reticulocyte volume	5e-10
GCST010241_356	Apolipoprotein A1 levels	6e-10
GCST90020026_93	Hip index	2e-9
GCST90020028_1650	Hip circumference adjusted for BMI	2e-9
GCST012227_181	Hip circumference adjusted for BMI	6e-9
GCST90020025_1085	Waist-to-hip ratio adjusted for BMI	6e-9
GCST90020027_303	Waist-hip index	7e-9
GCST90020024_836	A body shape index	1e-8
GCST90020028_1653	Hip circumference adjusted for BMI	2e-8
GCST90020026_92	Hip index	4e-8
GCST90020028_1652	Hip circumference adjusted for BMI	4e-8
GCST010277_13	Gout	2e-7
GCST007733_24	Serum uric acid levels	3e-7
GCST007733_66	Serum uric acid levels	5e-6
GCST008972_6	Urate levels	5e-6

EFO canonical traits (from GWAS)

12 canonical traits:

EFO ID	Trait name
EFO:0005260	response to antimicrotubule agent
EFO:0006336	diastolic blood pressure
EFO:0004761	uric acid measurement
EFO:0004340	body mass index
EFO:0004531	urate measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects expression, decreases expression, increases abundance	3
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
Estradiol	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases methylation, increases expression	2
Valproic Acid	increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	decreases expression, affects cotreatment	1
dicrotophos	increases expression	1
bisphenol A	decreases methylation	1
hydroxyhydroquinone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
pyrrolidine dithiocarbamic acid	affects localization, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
Vorinostat	increases expression	1
Arsenic	decreases expression, increases abundance, increases expression	1
Atrazine	increases expression	1
Cadmium	decreases expression, increases abundance	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Glucose	affects localization, decreases reaction, affects reaction	1
Indomethacin	decreases expression, affects cotreatment	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9KF	Ubigene HEK293 MLXIP KO	Transformed cell line	Female
CVCL_SY56	HAP1 MLXIP (-) 1	Cancer cell line	Male
CVCL_XQ57	HAP1 MLXIP (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.