MLX

Summary

MLX (MAX dimerization protein MLX, HGNC:11645) is a protein-coding gene on chromosome 17q21.2, encoding Max-like protein X (Q9UH92). Transcription regulator. It is a selective cancer dependency (DepMap: 19.1% of cell lines).

The product of this gene belongs to the family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors. These factors form heterodimers with Mad proteins and play a role in proliferation, determination and differentiation. This gene product may act to diversify Mad family function by its restricted association with a subset of the Mad family of transcriptional repressors, namely, Mad1 and Mad4. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.

Source: NCBI Gene 6945 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 57 total — 2 pathogenic
• GTEx eGene: eQTL in 22 tissues, sQTL in 28 (q < 0.05)
• Phenotypes (HPO): 54
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 19.1% of screened cell lines
• Constraint (gnomAD): pLI 0.08 (LoF-tolerant), LOEUF 0.69 (unconstrained)
• MANE Select transcript: NM_198204
• Notable: 57 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11645
Approved symbol	MLX
Name	MAX dimerization protein MLX
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	MAD7, MXD7, bHLHd13
Ensembl gene	ENSG00000108788
Ensembl biotype	protein_coding
OMIM	602976
Entrez	6945

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 22 protein_coding, 22 nonsense_mediated_decay, 7 retained_intron

MANE Select: ENST00000435881

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 3, TSL 5: 2

ENST00000435881, ENST00000246912, ENST00000346833, ENST00000585403, ENST00000586393, ENST00000588320, ENST00000590050, ENST00000590084, ENST00000591024, ENST00000591195, ENST00000592717, ENST00000873680, ENST00000913726, ENST00000913727, ENST00000913728, ENST00000913729, ENST00000913730, ENST00000913731, ENST00000948562, ENST00000981048, ENST00001054122, ENST00001054123, ENST00001054124, ENST00001054125, ENST00001054126, ENST00001054127, ENST00001054128, ENST00001054131, ENST00001054132, ENST00001054133, ENST00001054134, ENST00001054135, ENST00001054136, ENST00001054137, ENST00001054138, ENST00001073968, ENST00001073969, ENST00001073971, ENST00001073972, ENST00001073973, ENST00001094544, ENST00001094545, ENST00001094546, ENST00001094547, ENST00001094548, ENST00001094549, ENST00001094550, ENST00001094551, ENST00001094552, ENST00001094553, ENST00001137058

RefSeq mRNA: 3 — MANE Select: NM_198204 NM_170607, NM_198204, NM_198205

CCDS: CCDS11430, CCDS42341, CCDS45687

Canonical transcript exons

ENST00000435881 — 8 exons

Exon	Start	End
ENSE00000865357	42568470	42568559
ENSE00001222947	42567100	42567166
ENSE00003588467	42567619	42567655
ENSE00003602779	42569507	42569606
ENSE00003608840	42569204	42569303
ENSE00003634454	42569982	42570183
ENSE00003678369	42568837	42568943
ENSE00003904900	42571547	42573203

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.2551 / max 136.6561, expressed in 1819 samples.

Highest expression (Bgee): oocyte, secondary oocyte, parotid gland, duodenum, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

MLX is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 22 tissues and its splicing (sQTL) in 28 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 50 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	2.2e-30	+0.79	17:42577338:CTG:C
Whole Blood	sqtl	6.2e-28	-0.33	17:42549055:C:T
Adipose Subcutaneous	sqtl	1.0e-27	-0.32	17:42549055:C:T
Cells Cultured fibroblasts	sqtl	9.4e-27	-0.65	17:42549055:C:T
Muscle Skeletal	sqtl	7.7e-24	-0.36	17:42568614:G:A
Skin Sun Exposed Lower leg	sqtl	2.4e-23	-0.30	17:42628829:C:T
Artery Tibial	sqtl	6.2e-22	-0.35	17:42568614:G:A
Cells EBV-transformed lymphocytes	sqtl	9.3e-20	-0.73	17:42549055:C:T
Nerve Tibial	sqtl	1.7e-17	-0.29	17:42549055:C:T
Adipose Visceral Omentum	sqtl	3.5e-17	-0.33	17:42549055:C:T
Artery Aorta	sqtl	6.9e-16	-0.40	17:42564217:C:T
Thyroid	sqtl	8.6e-15	-0.29	17:42554255:C:A
Skin Not Sun Exposed Suprapubic	sqtl	4.8e-14	-0.29	17:42637020:C:T
Esophagus Mucosa	sqtl	1.6e-13	-0.34	17:42554255:C:A
Lung	sqtl	2.4e-13	-0.25	17:42554255:C:A
Breast Mammary Tissue	sqtl	6.1e-13	-0.33	17:42554255:C:A
Colon Transverse	sqtl	1.2e-11	-0.35	17:42554255:C:A
Esophagus Mucosa	eqtl	2.6e-09	+0.66	17:42454602:C:A
Muscle Skeletal	eqtl	1.8e-08	+0.63	17:42570448:T:C
Thyroid	eqtl	3.2e-06	+0.14	17:42448301:A:C

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
160964	28.7742	1819
208199	1.1015	825
160963	0.7761	534
160965	0.4462	220
160966	0.1571	64

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.01	gold quality
secondary oocyte	CL:0000655	97.00	gold quality
parotid gland	UBERON:0001831	96.15	gold quality
duodenum	UBERON:0002114	95.65	gold quality
mucosa of transverse colon	UBERON:0004991	95.65	gold quality
apex of heart	UBERON:0002098	95.54	gold quality
colonic mucosa	UBERON:0000317	95.53	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.31	gold quality
jejunal mucosa	UBERON:0000399	95.23	gold quality
ileal mucosa	UBERON:0000331	95.18	gold quality
rectum	UBERON:0001052	95.16	gold quality
heart left ventricle	UBERON:0002084	95.02	gold quality
cardiac ventricle	UBERON:0002082	95.01	gold quality
gastrocnemius	UBERON:0001388	94.80	gold quality
granulocyte	CL:0000094	94.76	gold quality
muscle of leg	UBERON:0001383	94.65	gold quality
heart right ventricle	UBERON:0002080	94.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.61	gold quality
left ventricle myocardium	UBERON:0006566	94.57	gold quality
monocyte	CL:0000576	94.54	gold quality
diaphragm	UBERON:0001103	94.54	gold quality
muscle organ	UBERON:0001630	94.45	gold quality
mononuclear cell	CL:0000842	94.43	gold quality
leukocyte	CL:0000738	94.42	gold quality
transverse colon	UBERON:0001157	94.31	gold quality
myocardium	UBERON:0002349	94.28	gold quality
gingival epithelium	UBERON:0001949	94.26	gold quality
gluteal muscle	UBERON:0002000	94.26	gold quality
body of stomach	UBERON:0001161	94.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.23	gold quality
blood	UBERON:0000178	94.20	gold quality
vastus lateralis	UBERON:0001379	94.16	gold quality
lower lobe of lung	UBERON:0008949	94.06	gold quality
body of pancreas	UBERON:0001150	94.05	gold quality
esophagus squamous epithelium	UBERON:0006920	94.01	gold quality
triceps brachii	UBERON:0001509	93.99	gold quality
quadriceps femoris	UBERON:0001377	93.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.92	gold quality
skeletal muscle tissue	UBERON:0001134	93.89	gold quality
heart	UBERON:0000948	93.85	gold quality
small intestine	UBERON:0002108	93.84	gold quality
deltoid	UBERON:0001476	93.81	gold quality
epithelium of esophagus	UBERON:0001976	93.70	gold quality
right atrium auricular region	UBERON:0006631	93.68	gold quality
biceps brachii	UBERON:0001507	93.66	gold quality
cardiac atrium	UBERON:0002081	93.63	gold quality
body of tongue	UBERON:0011876	93.63	gold quality
nephron tubule	UBERON:0001231	93.59	gold quality
islet of Langerhans	UBERON:0000006	93.53	gold quality
muscle tissue	UBERON:0002385	93.49	gold quality
cardia of stomach	UBERON:0001162	93.48	gold quality
squamous epithelium	UBERON:0006914	93.48	gold quality
metanephros cortex	UBERON:0010533	93.47	gold quality
upper lobe of lung	UBERON:0008948	93.42	gold quality
jejunum	UBERON:0002115	93.40	gold quality
right adrenal gland	UBERON:0001233	93.38	gold quality
right adrenal gland cortex	UBERON:0035827	93.38	gold quality
upper lobe of left lung	UBERON:0008952	93.36	gold quality
gingiva	UBERON:0001828	93.28	gold quality
right lobe of liver	UBERON:0001114	93.26	gold quality
pancreas	UBERON:0001264	93.22	gold quality
amniotic fluid	UBERON:0000173	93.13	gold quality
right lobe of thyroid gland	UBERON:0001119	93.07	gold quality
left adrenal gland	UBERON:0001234	93.07	gold quality
left adrenal gland cortex	UBERON:0035825	92.95	gold quality
esophagus mucosa	UBERON:0002469	92.94	gold quality
tongue squamous epithelium	UBERON:0006919	92.94	gold quality
stomach	UBERON:0000945	92.92	gold quality
right lung	UBERON:0002167	92.80	gold quality
intestine	UBERON:0000160	92.78	gold quality
superficial temporal artery	UBERON:0001614	92.77	gold quality
adrenal cortex	UBERON:0001235	92.73	gold quality
large intestine	UBERON:0000059	92.72	gold quality
lymph node	UBERON:0000029	92.69	gold quality
left lobe of thyroid gland	UBERON:0001120	92.66	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.66	gold quality
colon	UBERON:0001155	92.63	gold quality
saliva-secreting gland	UBERON:0001044	92.60	gold quality
spleen	UBERON:0002106	92.60	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.56	gold quality
liver	UBERON:0002107	92.51	gold quality
adipose tissue	UBERON:0001013	92.46	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.42	gold quality
vena cava	UBERON:0004087	92.36	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.36	gold quality
omental fat pad	UBERON:0010414	92.34	gold quality
peritoneum	UBERON:0002358	92.33	gold quality
minor salivary gland	UBERON:0001830	92.30	gold quality
connective tissue	UBERON:0002384	92.30	gold quality
tibialis anterior	UBERON:0001385	92.26	gold quality
tongue	UBERON:0001723	92.23	gold quality
mouth mucosa	UBERON:0003729	92.22	gold quality
thyroid gland	UBERON:0002046	92.11	gold quality
pancreatic ductal cell	CL:0002079	92.10	gold quality
adrenal gland	UBERON:0002369	92.07	gold quality
fundus of stomach	UBERON:0001160	92.06	gold quality
gall bladder	UBERON:0002110	91.93	gold quality
lower esophagus mucosa	UBERON:0035834	91.85	gold quality
kidney epithelium	UBERON:0004819	91.70	gold quality
skin of leg	UBERON:0001511	91.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.32
E-HCAD-10	yes	7.27

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tongue	tissue	80.6
Skeletal muscle	tissue	54.6	low
Liver	tissue	48.1	low
Duodenum	tissue	44.7	medium
Heart muscle	tissue	44.0	low
Spinal cord	tissue	41.3
Small intestine	tissue	39.8	medium
Corpus callosum	tissue	38.1
Rectum	tissue	36.5	medium
Colon	tissue	36.1	medium
Medulla oblongata	tissue	32.4
Midbrain	tissue	31.6
Pancreas	tissue	30.6	medium
Superior colliculi	tissue	30.0
Substantia nigra	tissue	29.8
Pons	tissue	29.5
Adipose tissue	tissue	29.2	medium
Stomach 1	tissue	28.1	medium
Thymus	tissue	28.1
Putamen	tissue	27.7
Tonsil	tissue	27.6	medium
Thalamus	tissue	27.4
Kidney	tissue	26.7	medium
Esophagus	tissue	26.6	low
Lung	tissue	26.3	medium
Urinary bladder	tissue	26.1	medium
Lymph node	tissue	25.7	not detected
Salivary gland	tissue	23.3	medium
Frontal cortex	tissue	23.2
Hypothalamus	tissue	23.2
Thyroid gland	tissue	23.2	low
Ventral forebrain	tissue	22.3
Cerebral cortex	tissue	22.0	medium
Somatosensory cortex	tissue	22.0
Hippocampal formation	tissue	21.8
Periaqueductal gray	tissue	21.6
Breast	tissue	21.5	low
Adrenal gland	tissue	21.5	medium
Septum	tissue	21.4
Vagina	tissue	20.8	low
Occipital cortex	tissue	20.6
Appendix	tissue	20.4	medium
Placenta	tissue	20.2	medium
Cerebellum	tissue	19.9	medium
Motor cortex	tissue	19.6
Basal ganglia	tissue	19.4	medium
Skin 1	tissue	19.2	medium
Gallbladder	tissue	19.1	medium
Smooth muscle	tissue	19.0	low
Spleen	tissue	19.0	not detected
Caudate putamen	tissue	18.7
Pituitary gland	tissue	18.5
Parathyroid gland	tissue	18.4	low
Amygdala	tissue	18.4
Entorhinal cortex	tissue	18.3
Temporal cortex	tissue	18.2
Cervix	tissue	18.1	low
Insular cortex	tissue	18.1
Prefrontal cortex	tissue	17.6
Retrosplenial cortex	tissue	17.4

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal spinal cord (41.3), Ventral spinal cord (39.9), White matter (38.1), Blood vessel (24.6), Dorsal hippocampus (21.8).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets:

Target	Regulation
ARNT
COL11A1
ODC1	Unknown
PKLR	Unknown
SLU7
TXNIP	Unknown

JASPAR motifs

Motif	Name	Family
MA0663.1	MLX	bHLH-ZIP
UN0905.1	MLX::ETV1	bHLH-ZIP,Ets-related
UN0906.1	MLX::FOXA1	bHLH-ZIP,FOX
UN0907.1	MLX::FOXD2	bHLH-ZIP,FOX
UN0908.1	MLX::TEAD4	bHLH-ZIP,TEF-1-related factors
UN1093.1	MLX::ELF2	bHLH-ZIP,Ets-related
UN1094.1	MLX::ETV4	bHLH-ZIP,Ets-related
UN1095.1	MLX::FLI1	bHLH-ZIP,Ets-related
UN1096.1	MLX::GABPA	bHLH-ZIP,Ets-related

JASPAR matrix evidence (PMIDs): PMID:14742444

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

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

showing 30 of 93 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-377-5P	99.70	65.28	712

Functional genomics

gnomAD constraint: pLI 0.0769, LOEUF 0.694, missense Z 0.618 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000435881 — one region, missense o/e 0.93. DepMap (CRISPR cell-line fitness): dependent in 19.1% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): NP 5 (-1.322), MM485 (-1.214), NCI-H1573 (-1.065), UM-RC-3 (-1.018), EJM (-0.976), C75 (-0.969), SNU-245 (-0.957), JHUEM-1 (-0.953), WM88 (-0.95), SUM-52PE (-0.947), C-33 A (-0.927), JVE-015 (-0.923), NCI-H522 (-0.913), Li-7 (-0.895), SCaBER (-0.891).

Literature-anchored findings (GeneRIF, showing 9)

• 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)
• Mlx is an obligatory partner of ChREBP in regulating lipogenic enzyme genes in liver. (PMID:15664996)
• 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)
• MYC is part of a network of bHLHLZ proteins centered on the MYC heterodimeric partner MAX and its counterpart, the MAX-like protein MLX. (PMID:24857747)
• Knockdown of MondoA, or its dimerization partner Mlx, blocks Myc-induced reprogramming of multiple metabolic pathways, resulting in apoptosis (PMID:25640402)
• MLX-Q139R mutation plays a crucial role in the pathogenesis of Takayasu arteritis through promoting inflammasome formation. (PMID:30354298)
• The MNT transcription factor autoregulates its expression and supports proliferation in MYC-associated factor X (MAX)-deficient cells. (PMID:31919096)
• MLX plays a key role in lipid and glucose metabolism in humans: Evidence from in vitro and in vivo studies. (PMID:37088121)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mlx	ENSDARG00000037891
mus_musculus	Mlx	ENSMUSG00000017801
rattus_norvegicus	Mlx	ENSRNOG00000019983
drosophila_melanogaster	bigmax	FBGN0039509

Paralogs (3): MLXIPL (ENSG00000009950), TFAP4 (ENSG00000090447), MLXIP (ENSG00000175727)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:108398) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 20 distinct phenotype terms.

Mouse phenotype (MP)	Records
male infertility	2
increased startle reflex	1
increased urine glucose level	1
abnormal seminiferous tubule morphology	1
decreased mean corpuscular volume	1
asthenozoospermia	1
oligozoospermia	1
increased lean body mass	1
decreased testis weight	1
decreased male germ cell number	1
decreased epididymis weight	1
decreased circulating glucose level	1
decreased mean corpuscular hemoglobin	1
teratozoospermia	1
increased circulating sodium level	1
decreased total body fat amount	1
increased bone mineral content	1
impaired skeletal muscle regeneration	1
increased fasting circulating glucose level	1
abnormal sperm progressive motility	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Xenopus borealis	Q07957	81.3%	Diamond
Caenorhabditis elegans	P41846	36.8%	Diamond

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
PSMC3IP	protein-coding	29893
HSD17B1	protein-coding	3292
NAGLU	protein-coding	4669
COASY	protein-coding	80347
HSD17B1-AS1	ncRNA	108783654
RETREG3	protein-coding	162427
TUBG1	protein-coding	7283

Protein

Protein identifiers

Max-like protein X — Q9UH92 (reviewed: Q9UH92)

Alternative names: Class D basic helix-loop-helix protein 13, Max-like bHLHZip protein, Protein BigMax, Transcription factor-like protein 4

All UniProt accessions (2): Q9UH92, K7EID0

UniProt curated annotations — full annotation on UniProt →

Function. Transcription regulator. Forms a sequence-specific DNA-binding protein complex with MAD1, MAD4, MNT, WBSCR14 and MLXIP which recognizes the core sequence 5’-CACGTG-3’. The TCFL4-MAD1, TCFL4-MAD4, TCFL4-WBSCR14 complexes are transcriptional repressors. 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 heterodimer with MAD1, MAD4, MNT, WBSCR14 and MLXIP. Can also bind DNA as a homodimer.

Subcellular location. Cytoplasm Cytoplasm Nucleus.

Tissue specificity. Expressed in all tissues tested, including spleen, thymus, prostate, ovary, intestine, colon, peripheral blood leukocyte, heart, liver, skeletal muscle and kidney. Lower levels of expression in testis, brain, placenta and lung.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UH92-1	Gamma	yes
Q9UH92-2	Alpha
Q9UH92-3	Beta

RefSeq proteins (3): NP_733752, NP_937847, NP_937848 (=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 (20 total): modified residue 6, compositionally biased region 4, region of interest 3, splice variant 2, sequence conflict 2, chain 1, domain 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UH92-F1	73.71	0.45

Human Protein Atlas

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

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol; nuclear membrane

Antibody reliability (HPA): IH approved · IF supported

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
Phosphoserine	45, 48, 74, 77, 98, 7

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-163765	ChREBP activates metabolic gene expression	—
R-HSA-163685	Integration of energy metabolism	—
R-HSA-1430728	Metabolism	—

MSigDB gene sets: 272 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE45365_NK_CELL_VS_BCELL_UP, TATTATA_MIR374, TGACCTY_ERR1_Q2, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, TGCTGAY_UNKNOWN, GENTILE_UV_HIGH_DOSE_DN, GENTILE_UV_RESPONSE_CLUSTER_D5, TATCTGG_MIR488, PEART_HDAC_PROLIFERATION_CLUSTER_UP, GOBP_CARBOHYDRATE_HOMEOSTASIS, TCCAGAG_MIR518C, SENESE_HDAC1_TARGETS_UP, AP2GAMMA_01, OSMAN_BLADDER_CANCER_DN

GO Biological Process (7): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), glucose homeostasis (GO:0042593), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (12): 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 repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Integration of energy metabolism	1
Metabolism	1

GO top-level categories

35 GO namespaces:

Category	Terms
cellular anatomical structure	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
DNA-templated transcription	2
transcription cis-regulatory region binding	2
protein dimerization activity	2
negative regulation of DNA-templated transcription	1
gene expression	1
RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
carbohydrate homeostasis	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
nucleic acid binding	1
transcription regulator activity	1
identical protein binding	1
DNA-binding transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
protein binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 14 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

14 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of DNA-templated transcription	BP	direct assay
negative regulation of transcription by RNA polymerase II	BP	mutant phenotype
positive regulation of transcription by RNA polymerase II	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
DNA binding	MF	direct assay
DNA-binding transcription repressor activity, RNA polymerase II-specific	MF	direct assay
RNA polymerase II transcription regulatory region sequence-specific DNA binding	MF	direct assay
RNA polymerase II-specific DNA-binding transcription factor binding	MF	physical interaction
protein heterodimerization activity	MF	physical interaction
protein homodimerization activity	MF	physical interaction
sequence-specific double-stranded DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 460 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MLX	MXD4	Q14582	907
MLX	MNT	Q99583	828
MLX	NTRK1	P04629	770
MLX	NIF3L1	Q9GZT8	757
MLX	HSD17B1	P14061	705
MLX	PKLR	P11973	639
MLX	XPO1	O14980	552
MLX	ZNF92	Q03936	550
MLX	LIPN	Q5VXI9	549
MLX	SIN3A	Q96ST3	497
MLX	PKM	P14618	427
MLX	MXI1	P50539	422
MLX	SP6	Q3SY56	390
MLX	PCSK5	Q92824	387
MLX	MLXIP	Q9HAP2	385

IntAct

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

13 partners by confidence:

Partner	Interaction type	MIscore	Records
GABARAPL2	physical association	0.740	5
TLE5	physical association	0.670	4
HBZ	physical association	0.560	3
RBM39	physical association	0.560	3
ZBTB32	physical association	0.560	3
ECE1	physical association	0.370	2
CCL5	physical association	0.370	1
TNFSF14	physical association	0.370	1
BACH1	association	0.350	1
MGA	association	0.350	1
CCT6A	physical association	0.000	1
ID3	physical association	0.000	1
SAP30BP	physical association	0.000	1

BioGRID (100 interactions; top human partners by supporting records): MLXIP (Reconstituted Complex; 8 records), MLXIPL (Affinity Capture-MS; 7 records), MNT (Affinity Capture-MS; 6 records), GABARAPL2 (Two-hybrid; 3 records), AES (Two-hybrid; 2 records), AMPD2 (Affinity Capture-MS; 2 records), BACH1 (Affinity Capture-MS; 2 records), CSNK2A1 (Affinity Capture-MS; 2 records), CSNK2A2 (Affinity Capture-MS; 2 records), CSPG5 (Affinity Capture-MS; 2 records), MGA (Affinity Capture-MS; 2 records), MTCH2 (Proximity Label-MS; 2 records), MXD1 (Two-hybrid; 2 records), MXD4 (Two-hybrid; 2 records), SNX1 (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

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

Disease & clinical

Genetic variants

Variant evidence for MLX: 57 ClinVar records (2 pathogenic / likely pathogenic); 8 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	34
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (2)

Showing all 2 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
812136	NM_016556.4(PSMC3IP):c.614del (p.Glu205fs)	Pathogenic	criteria provided, single submitter	1
30741	NM_016556.4(PSMC3IP):c.600_602del	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore MLX’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; 15 predictions of 731):

Position(s)	Effect	Δscore	Sites
17:42567656–42567657	donor_loss	1.0000	2
17:42568824	acceptor_gain	1.0000
17:42568828	acceptor_gain	1.0000
17:42568932	donor_gain	1.0000
17:42568944–42568945	donor_loss	1.0000	5
17:42568953	donor_gain	1.0000
17:42569276	donor_gain	1.0000
17:42569316	donor_gain	1.0000
17:42569602	donor_gain	1.0000
17:42571532	acceptor_gain	1.0000

AlphaMissense

727 missense substitutions predicted likely pathogenic (of 1,633 scored), across 166 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
M211	9	0.875	0.992
H134	8	0.997	1.000
S172	8	0.961	0.999
F242	8	0.941	0.992
F253	8	0.939	0.996
F262	8	0.929	0.990
D182	8	0.887	0.982
D114	8	0.844	0.966
D111	8	0.824	0.960
D112	8	0.763	0.930
R141	7	0.999	1.000
R142	7	0.998	1.000
E138	7	0.997	0.999
W272	7	0.995	0.999
I145	7	0.977	1.000
F250	7	0.973	0.991
F186	7	0.967	0.997
E274	7	0.960	0.988
C159	7	0.951	0.994
F239	7	0.941	0.982

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.74e-07
Liver Hepatocellular Carcinoma (validation)	unfavorable	4.81e-06
Breast Invasive Carcinoma (TCGA)	unfavorable	0.000577

Disease associations

OMIM: gene MIM:602976 | disease phenotypes: MIM:614324

GenCC curated gene-disease

Mondo (1): ovarian dysgenesis 3 (MONDO:0013689)

Orphanet (1): 46,XX gonadal dysgenesis (Orphanet:243)

HPO phenotypes

54 phenotypes (HPO-id order):

HPO	Term
HP:0000488	Retinopathy
HP:0000505	Visual impairment
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001297	Stroke
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001646	Abnormal aortic valve morphology
HP:0001654	Abnormal heart valve morphology
HP:0001658	Myocardial infarction
HP:0001659	Aortic regurgitation
HP:0001824	Weight loss
HP:0001903	Anemia
HP:0001920	Renal artery stenosis
HP:0001945	Fever
HP:0002039	Anorexia
HP:0002076	Migraine
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002105	Hemoptysis
HP:0002167	Abnormal speech pattern
HP:0002315	Headache
HP:0002321	Vertigo
HP:0002326	Transient ischemic attack
HP:0002617	Vascular dilatation
HP:0002633	Vasculitis
HP:0002637	Cerebral ischemia
HP:0002829	Arthralgia
HP:0003326	Myalgia
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0004306	Abnormal endocardium morphology
HP:0004372	Reduced consciousness
HP:0004417	Intermittent claudication
HP:0004970	Ascending tubular aorta aneurysm
HP:0005244	Gastrointestinal infarctions
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0012089	Arteritis
HP:0012219	Erythema nodosum
HP:0012378	Fatigue
HP:0012649	Increased inflammatory response
HP:0020141	Blood pressure substantially higher in legs than arms
HP:0030166	Night sweats
HP:0032554	Absent pulse
HP:0033834	Malaise
HP:0100545	Arterial stenosis
HP:0100576	Amaurosis fugax
HP:0100735	Hypertensive crisis
HP:0100749	Chest pain
HP:0100758	Gangrene
HP:0200042	Skin ulcer
HP:6000944	Carotidynia
HP:6000945	Asymmetric blood pressure between arms

GWAS associations

8 associations:

Study	Trait	p-value
GCST009379_58	Type 2 diabetes	2e-12
GCST90020025_256	Waist-to-hip ratio adjusted for BMI	6e-9
GCST90020027_1228	Waist-hip index	9e-9
GCST007515_29	Type 2 diabetes	2e-8
GCST000879_25	Crohn’s disease	3e-8
GCST010766_1	Type 2 diabetes (time to event)	3e-8
GCST007847_104	Type 2 diabetes	4e-8
GCST007847_120	Type 2 diabetes	2e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0004918	age at diagnosis
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2062357 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 293 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2063869	GDC-0152	1	293

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

8 measured of 8 human assays (8 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL2063869	IC50	10 nM
CHEMBL2063868	KI	35 nM
CHEMBL2063863	KI	190 nM
CHEMBL2063866	KI	410 nM
CHEMBL2063862	KI	430 nM
CHEMBL2063867	KI	700 nM
CHEMBL2063865	KI	800 nM
CHEMBL2063864	KI	7600 nM

ChEMBL bioactivities

8 potent at pChembl≥5 of 8 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.85	Ki	14	nM	GDC-0152
7.80	Ki	16	nM	CHEMBL2063868
7.52	Ki	30	nM	CHEMBL2063862
7.52	Ki	30	nM	CHEMBL2063863
7.16	Ki	70	nM	CHEMBL2063866
7.10	Ki	80	nM	CHEMBL2063865
7.05	Ki	90	nM	CHEMBL2063867
6.34	Ki	460	nM	CHEMBL2063864

PubChem BioAssay actives

8 with measured affinity, of 8 total; 8 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
(2S)-1-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino]acetyl]-N-(4-phenylthiadiazol-5-yl)pyrrolidine-2-carboxamide	676467: Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	ki	0.0140	uM
(2S)-1-[(2S)-2-[[(2S)-2-(methylamino)propanoyl]amino]-2-phenylacetyl]-N-(4-phenylthiadiazol-5-yl)pyrrolidine-2-carboxamide	676467: Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	ki	0.0160	uM
(2S)-N-(2,2-diphenylethyl)-1-[(2S)-3-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]pyrrolidine-2-carboxamide	676467: Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	ki	0.0300	uM
(4R)-3-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino]acetyl]-N-(2,2-diphenylethyl)-1,3-thiazolidine-4-carboxamide	676467: Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	ki	0.0300	uM
(2S)-1-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino]acetyl]-N-(2,2-diphenylethyl)pyrrolidine-2-carboxamide	676467: Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	ki	0.0700	uM
(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2,3-dihydroxypropyl]amino]propanoyl]amino]-3-methylbutanoyl]-N-(2,2-diphenylethyl)pyrrolidine-2-carboxamide	676467: Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	ki	0.0800	uM
(2S)-N-[(4-chlorophenyl)methyl]-1-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino]acetyl]pyrrolidine-2-carboxamide	676467: Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	ki	0.0900	uM
(2S)-1-[(2S)-2-[[(2S)-2-(cyclopropylmethylamino)propanoyl]amino]-3-methylbutanoyl]-N-(2,2-diphenylethyl)pyrrolidine-2-carboxamide	676467: Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	ki	0.4600	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases stability, decreases expression	3
Air Pollutants	affects expression, increases abundance, decreases expression	2
Smoke	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Vanadates	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2066545	Binding	Displacement of 5-FAM-conjugated AVP-diPhe-FAM from MLXBIR3SG after 30 mins by fluorescence polarization-based competition assay	Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152). — *J Med Chem*

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for MLX across ~30M SureChEMBL compounds — explore on Sugi Predict.