TRPM6

Summary

TRPM6 (transient receptor potential cation channel subfamily M member 6, HGNC:17995) is a protein-coding gene on chromosome 9q21.13, encoding Transient receptor potential cation channel subfamily M member 6 (Q9BX84). Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain.

This gene is predominantly expressed in the kidney and colon, and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis, and plays an essential role in epithelial magnesium transport and in the active magnesium absorption in the gut and kidney. Mutations in this gene are associated with hypomagnesemia with secondary hypocalcemia. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 140803 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intestinal hypomagnesemia 1 (Strong, GenCC)
• GWAS associations: 15
• Clinical variants (ClinVar): 971 total — 36 pathogenic, 32 likely-pathogenic
• Phenotypes (HPO): 7
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_017662

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17995
Approved symbol	TRPM6
Name	transient receptor potential cation channel subfamily M member 6
Location	9q21.13
Locus type	gene with protein product
Status	Approved
Aliases	CHAK2, FLJ22628
Ensembl gene	ENSG00000119121
Ensembl biotype	protein_coding
OMIM	607009
Entrez	140803

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000359047, ENST00000360774, ENST00000361255, ENST00000449912, ENST00000483186, ENST00000715553

RefSeq mRNA: 3 — MANE Select: NM_017662 NM_001177310, NM_001177311, NM_017662

CCDS: CCDS55318, CCDS55319, CCDS6647

Canonical transcript exons

ENST00000360774 — 39 exons

Exon	Start	End
ENSE00000803811	74738407	74738612
ENSE00000803812	74739367	74739449
ENSE00000803813	74739723	74740009
ENSE00000803826	74796741	74796893
ENSE00000803827	74800254	74800482
ENSE00000803828	74801898	74802175
ENSE00000803829	74803794	74803886
ENSE00000917547	74742561	74742626
ENSE00000917548	74744095	74744145
ENSE00000917549	74750664	74750722
ENSE00000917550	74752277	74752368
ENSE00000917551	74755353	74755473
ENSE00000917552	74761696	74761808
ENSE00000917558	74782362	74782476
ENSE00000917559	74782679	74782853
ENSE00000917560	74785874	74786125
ENSE00000917561	74788614	74788742
ENSE00000917562	74792624	74792770
ENSE00000917563	74808034	74808174
ENSE00000917564	74810815	74810868
ENSE00000917565	74812299	74812433
ENSE00000917566	74816669	74816769
ENSE00000917567	74816892	74816964
ENSE00000982817	74858669	74858748
ENSE00000982818	74855527	74855565
ENSE00000982819	74842166	74842343
ENSE00000982820	74840024	74840237
ENSE00000982821	74833998	74834122
ENSE00000982825	74732685	74732736
ENSE00001023893	74775883	74776076
ENSE00001172471	74771703	74771835
ENSE00001198712	74761999	74763134
ENSE00001376333	74722495	74724746
ENSE00001376878	74747889	74747914
ENSE00001783514	74728239	74728345
ENSE00003307486	74820304	74820427
ENSE00003506662	74821669	74821837
ENSE00003671042	74827778	74827949
ENSE00003848240	74887824	74887921

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 92.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2613 / max 86.7396, expressed in 48 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101017	0.1682	25
101016	0.0930	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic mucosa	UBERON:0000317	92.25	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.23	gold quality
jejunal mucosa	UBERON:0000399	90.70	gold quality
rectum	UBERON:0001052	87.18	gold quality
mucosa of transverse colon	UBERON:0004991	83.78	gold quality
hair follicle	UBERON:0002073	83.74	silver quality
duodenum	UBERON:0002114	82.28	gold quality
mucosa of paranasal sinus	UBERON:0005030	80.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.31	gold quality
gingival epithelium	UBERON:0001949	76.10	silver quality
ileal mucosa	UBERON:0000331	76.02	silver quality
diaphragm	UBERON:0001103	75.22	gold quality
corpus callosum	UBERON:0002336	74.38	gold quality
superficial temporal artery	UBERON:0001614	74.00	gold quality
blood	UBERON:0000178	73.77	gold quality
transverse colon	UBERON:0001157	71.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	70.77	gold quality
tongue squamous epithelium	UBERON:0006919	70.32	gold quality
epithelium of nasopharynx	UBERON:0001951	70.28	gold quality
spinal cord	UBERON:0002240	69.24	gold quality
gingiva	UBERON:0001828	69.01	silver quality
pigmented layer of retina	UBERON:0001782	68.52	gold quality
bone marrow cell	CL:0002092	68.31	silver quality
jejunum	UBERON:0002115	68.22	gold quality
oocyte	CL:0000023	66.91	gold quality
large intestine	UBERON:0000059	66.87	gold quality
bone marrow	UBERON:0002371	66.85	gold quality
intestine	UBERON:0000160	66.11	gold quality
colonic epithelium	UBERON:0000397	66.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	2043.64
E-GEOD-125970	yes	22.91
E-ANND-3	yes	7.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS

miRNA regulators (miRDB)

91 targeting TRPM6, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• Deficiency /mutations of TRPM6 causes hypomagnesemia with secondary hypocalcemia (PMID:12032568)
• Individuals with TRPM6 mutations have abnormal renal magnesium excretion. Deficiency causes hypomagnesemia with secondary hypocalcemia. (PMID:12032570)
• TRPM6 is specifically localized along the apical membrane of the renal distal convoluted tubule and the brush-border membrane of the small intestine and is specific for Mg2+ absoprtion. (PMID:14576148)
• TRPM6 specifically interacted with its closest homolog, the Mg(2+)-permeable cation channel TRPM7, resulting in the assembly of functional TRPM6/TRPM7 complexes at the cell surface. (PMID:14976260)
• In patients with primary hypomagnesaemia and secondary hypocalcaemia (HSH), a combined defect of intestinal magnesium absorption and renal magnesium conservation TRPM6 is the first component involved directly in epithelial magnesium reabsorption[review] (PMID:16075242)
• Although TRPM6 and TRPM7 are closely related and deficiency in either one of these molecules severely affects Mg(2+) homeostasis regulation, TRPM6 and TRPM7 do not appear to be functionally redundant. (PMID:16150690)
• heterologous expression of TRPM6 but not the mutant TRPM6(S141L) produces functional channels with divalent cation permeability profile and pH sensitivity distinctive from those of TRPM7 channels and TRPM6/7 complexes (PMID:16636202)
• data demonstrate that amino acid residues E1024, I1030 and D1031 are important for channel function and that subtle amino acid variation in the pore region accounts for TRPM6 permeation properties (PMID:17098283)
• TRPM6 mutants are found in patients with a rare but severe hereditary disease called hypomagnesaemia with secondary hypocalcaemia –{REVIEW} (PMID:17217065)
• This review discusses the importance of magnesium in vascular biology and implications in hypertension and highlights the transport systems, particularly TRPM6–REVIEW (PMID:18192217)
• The predominant Mg transporters include TRPM6 and TRPM7 (PMID:18301276)
• findings support a model where massive autophosphorylation outside the catalytic domain of TRPM6 and TRPM7 may facilitate kinase-substrate interactions leading to enhanced phosphorylation of those substrates (PMID:18365021)
• intracellular ATP regulates TRPM6 channel activity via its alpha-kinase domain independently of alpha-kinase activity (PMID:18490453)
• diverse molecular regulation of TRPM6 by magnesiotropic hormones, intracellular factors and its fused alpha-kinase domain disclosed novel regulatory mechanisms of active magnesium reabsorption–REVIEW (PMID:18660673)
• TRPM6 and TRPM7 phosphorylate the assembly domain of myosin IIA, IIB and IIC on identical residues. (PMID:18675813)
• These findings clearly outline the activation of TRPM6 by EGF, a process fundamental to Mg2+ homeostasis. (PMID:19073827)
• Our results provide suggestive evidence that two common non-synonymous TRPM6 coding region variants, Ile1393Val and Lys1584Glu polymorphisms, might confer susceptibility to type 2 diabetes in women with low magnesium intake (PMID:19149903)
• REA operates as a negative feedback modulator of TRPM6 in the regulation of active Mg(2+) (re)absorption and provides new insight into the molecular mechanism of renal transepithelial Mg(2+) transport. (PMID:19329436)
• Up-regulation of TRPM6 transcriptional activity by AP-1 in renal epithelial cells. (PMID:19937979)
• Loss-of-function mutations cause hypomagnesemia with secondary hypocalcemia. (PMID:20395377)
• The present investigation further suggests that TRPM6 and TRPM7 gene variation may not be useful predictors for type 2 diabetes mellitus risk assessment. (PMID:20875900)
• Results suggest that TRPM6 expression is up-regulated by a PI3K/Akt/mTOR pathway . (PMID:21073857)
• A novel mutation of TRPM6 gene is responsible for the development of familial hypommagnesaemia in Turkish children. (PMID:21669885)
• PIP2 is required for TRPM6 channel function; hydrolysis of PIP2 by PLC-coupled hormones/agonists may constitute an important pathway for TRPM6 gating, and perhaps Mg2+ homeostasis. (PMID:22180838)
• Alteration in the expression and/or activity of magnesium channels is a frequent finding in cancer cells. (PMID:22671428)
• Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy (PMID:22733750)
• Case Report: Resolving basal ganglia calcification in hereditary hypomagnesemia with secondary hypocalcemia due to a novel TRPM6 gene mutation. (PMID:22982920)
• Two novel mutations in Chinese sisters with familial hypomagnesemia with secondary hypocalcemia were found: one frameshift mutation (c.1196delC) and one non-sense mutation (c.4577G>A). Both patients were compound heterozygotes for these mutations. (PMID:23689795)
• We conclude that the new TRPM6 missense mutations lead to dysregulated intestinal/renal Mg(2+) (re)absorption as a consequence of loss of TRPM6 channel function. (PMID:23942199)
• TRPM6 modulates the functionality of TRPM7, and the TRPM6 kinase plays a critical role in tuning the phenotype of the TRPM7.M6 channel complex. (PMID:24385424)
• TRPM6 kinase activity is linked to channel activity through a kinase-independent mechanism involving the dimerization motif binding to a pocket within the kinase domain. (PMID:24650431)
• Data indicate heteromer formation between channel kinases TRPM6 and TRPM7 influences the biological activity of the ion channels. (PMID:24858416)
• Knowledge of TRPM6 functioning is of vital importance to decipher its role in Mg handling and will, in particular, provide a molecular basis for achieving a better understanding of Mg mal(re)absorption and hence systemic Mg balance. (PMID:24906182)
• N-Myc can promote neuroblastoma cell proliferation through up-regulation of the channel kinases TRPM6 and TRPM7 (PMID:25277194)
• TRPM6 mRNA and protein levels in atrial fibrillation group were elevated markedly in comparison with sinus rhythm group. (PMID:25796343)
• we showed that two serum magnesium associated loci, MUC1 and TRPM6, had significant effect modification with progestin use and insulin levels, respectively, in European Americans. (PMID:26058915)
• The Different Roles of The Channel-Kinases TRPM6 and TRPM7 (PMID:26179995)
• Data show that resistant cells express lower amounts of the transient receptor potential cation channel subfamily M TRPM6 and 7, both involved in magnesium transport. (PMID:26563869)
• A homozygous frame-shift mutation in the TRPM6 gene is associated with Hereditary hypomagnesemia with secondary hypocalcemia. (PMID:26759217)
• TNF-alpha rescues the EGFR tyrosine kinase inhibitor-induced decrease in TRPM6 expression and Mg2+ influx mediated via the activation of an NF-kappaB signaling pathway. (PMID:27925186)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	trpm6	ENSDARG00000103454
mus_musculus	Trpm6	ENSMUSG00000024727
rattus_norvegicus	Trpm6	ENSRNOG00000013053
drosophila_melanogaster	Trpm	FBGN0265194
caenorhabditis_elegans	gon-2	WBGENE00001651
caenorhabditis_elegans		WBGENE00004149
caenorhabditis_elegans		WBGENE00020972
caenorhabditis_elegans		WBGENE00021404
caenorhabditis_elegans		WBGENE00021408

Paralogs (7): TRPM5 (ENSG00000070985), TRPM3 (ENSG00000083067), TRPM7 (ENSG00000092439), TRPM4 (ENSG00000130529), TRPM1 (ENSG00000134160), TRPM2 (ENSG00000142185), TRPM8 (ENSG00000144481)

Protein

Protein identifiers

Transient receptor potential cation channel subfamily M member 6 — Q9BX84 (reviewed: Q9BX84)

Alternative names: Channel kinase 2, Melastatin-related TRP cation channel 6

All UniProt accessions (2): Q9BX84, Q96LV9

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain. Crucial for Mg(2+) homeostasis. Has an important role in epithelial Mg(2+) transport and in the active Mg(2+) absorption in the gut and kidney. However, whether TRPM6 forms functional homomeric channels by itself or functions primarily as a subunit of heteromeric TRPM6-TRPM7 channels, is still under debate. The C-terminal kinase domain can be cleaved from the channel segment in a cell-type-specific fashion. The cleaved kinase fragments can translocate to the nucleus, and bind chromatin-remodeling complex proteins to ultimately phosphorylate specific Ser/Thr residues of histones known to be functionally important for cell differentiation and development.

Subunit / interactions. Homomers. Forms heteromers with TRPM7; TRPM6 increases the current amplitude of TRPM6/7 heteromers as compared to TRPM7 homomer. Interacts (via kinase domain) with RACK1.

Subcellular location. Cell membrane. Apical cell membrane Nucleus.

Tissue specificity. Highly expressed in kidney and colon. Isoform TRPM6a and isoform TRPM6b, are coexpressed with TRPM7 in kidney, and testis, and are also found in several cell lines of lung origin. Isoform TRPM6c is detected only in testis and in NCI-H510A small cell lung carcinoma cells.

Post-translational modifications. Autophosphorylated; autophosphorylation controlls the protein kinase activity of TRPM6 towards their substrates. Autophosphorylation of Thr-1851 in the kinase domain is essential for the inhibitory effect of RACK1. The C-terminus of TRPM6 is proteolytically cleaved in vivo, in a cell type-specific fashion, releasing the kinase module from the transmembrane domain. The cleaved kinase fragments are translocated to the nucleus to phosphorylate histones and regulate gene expression.

Disease relevance. Hypomagnesemia 1 (HOMG1) [MIM:602014] A disorder due to a primary defect in intestinal magnesium absorption. It is characterized by low levels of serum magnesium alongside with a normal renal magnesium secretion, secondary hypocalcemia and calcinocis. Affected individuals show neurologic symptoms of hypomagnesemic hypocalcemia, including seizures and muscle spasms, during infancy. Hypocalcemia is secondary to parathyroid failure resulting from magnesium deficiency. Untreated, the disorder may be fatal or may result in neurological damage. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Strongly inhibited by intracellular Mg(2+); unlikely to be active at physiological levels of intracellular Mg(2+). In the heteromeric TRPM6-TRPM7 channels complexes, TRPM7 are able to offset the very high sensitivity of TRPM6 to cytosolic Mg(2+) to physiologically relevant concentrations, whereas TRPM6 relieve TRPM7 from the inhibitory action of Mg-ATP. Consequently, the association of TRPM6 with TRPM7 allow for high constitutive activity of TRPM6/7 in the presence of physiological levels of Mg(2+) and Mg-ATP. The kinase activity is controlled through the autophosphorylation of a serine/threonine-rich region located to the N-terminal of the catalytic domain.

Miscellaneous. Lacks the ion channel region. Lacks the ion channel region. Lacks the ion channel region.

Similarity. In the C-terminal section; belongs to the protein kinase superfamily. Alpha-type protein kinase family. ALPK subfamily. In the N-terminal section; belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM6 sub-subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9BX84-1	TRPM6a	yes
Q9BX84-2	TRPM6b
Q9BX84-3	TRPM6c
Q9BX84-4	TRPM6t
Q9BX84-5	M6-kinase 1
Q9BX84-6	M6-kinase 2
Q9BX84-7	M6-kinase 3

RefSeq proteins (3): NP_001170781, NP_001170782, NP_060132* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004166	a-kinase_dom	Domain
IPR005821	Ion_trans_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR029597	TRPM6_a-kinase_dom	Domain
IPR032415	TRPM_tetra	Domain
IPR037162	TRPM_tetra_sf	Homologous_superfamily
IPR041491	TRPM_SLOG	Domain
IPR050927	TRPM	Family
IPR057366	TRPM-like	Domain

Pfam: PF00520, PF02816, PF16519, PF18139, PF25508

Catalyzed reactions (Rhea), 5 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• Zn(2+)(in) = Zn(2+)(out) (RHEA:29351)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Mg(2+)(in) = Mg(2+)(out) (RHEA:29827)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (68 total): sequence variant 19, binding site 12, topological domain 8, splice variant 8, transmembrane region 6, mutagenesis site 4, compositionally biased region 3, chain 2, region of interest 2, intramembrane region 1, domain 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BX84-F1	65.03	0.12

Functional residue map

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

Catalytic / active sites (1): 1923 (proton acceptor)

Ligand- & substrate-binding residues (12): 1777; 1778; 1779; 1780; 1804; 1876; 1879; 1909; 1933; 1966; 1968; 1972

Post-translational modifications (1): 1851

Mutagenesis-validated functional residues (4):

Position	Phenotype
1063–1065	abolishes channel activity. abolishes endogenous protein cleavage.
1804	abolishes kinase activity but does not affect expression levels or binding to rack1.
1851	significantly decreases autophosphorylation. does not alter binding to rack1 but prevents inhibition by rack1.
1851	significantly decreases autophosphorylation. does not alter binding to rack1 or inhibition by rack1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3295583	TRP channels

MSigDB gene sets: 151 (showing top): GOBP_MAGNESIUM_ION_TRANSPORT, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, GOCC_APICAL_PLASMA_MEMBRANE, SABATES_COLORECTAL_ADENOMA_DN, GOBP_RESPONSE_TO_TOXIC_SUBSTANCE, SOX5_01, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_PROTEIN_TETRAMERIZATION, GOBP_TRANSMEMBRANE_TRANSPORT, GOCC_CELL_PROJECTION_MEMBRANE, GOCC_APICAL_PART_OF_CELL, GOCC_CLUSTER_OF_ACTIN_BASED_CELL_PROJECTIONS, CTGAGCC_MIR24, GOCC_PLASMA_MEMBRANE_REGION

GO Biological Process (11): calcium ion transport (GO:0006816), response to toxic substance (GO:0009636), protein tetramerization (GO:0051262), calcium ion transmembrane transport (GO:0070588), monoatomic cation transmembrane transport (GO:0098655), magnesium ion transmembrane transport (GO:1903830), protein phosphorylation (GO:0006468), monoatomic ion transport (GO:0006811), metal ion transport (GO:0030001), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (15): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), calcium channel activity (GO:0005262), ATP binding (GO:0005524), calcium ion transmembrane transporter activity (GO:0015085), magnesium ion transmembrane transporter activity (GO:0015095), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (5): nucleus (GO:0005634), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), brush border membrane (GO:0031526), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Stimuli-sensing channels	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	2
monoatomic cation transmembrane transport	2
monoatomic cation transport	2
transport	2
protein kinase activity	2
metal ion transmembrane transporter activity	2
monoatomic cation transmembrane transporter activity	2
response to chemical	1
protein complex oligomerization	1
calcium ion transport	1
monoatomic ion transmembrane transport	1
magnesium ion transport	1
phosphorylation	1
protein modification process	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
calcium ion transmembrane transport	1
magnesium ion transmembrane transport	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic ion channel activity	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1

Protein interactions and networks

STRING

938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRPM6	CLDN16	Q9Y5I7	828
TRPM6	CLDN19	Q8N6F1	809
TRPM6	SLC41A1	Q8IVJ1	799
TRPM6	SLC41A3	Q96GZ6	791
TRPM6	TRPV5	Q9NQA5	786
TRPM6	CNNM2	Q9H8M5	780
TRPM6	SLC41A2	Q96JW4	755
TRPM6	TRPM7	Q96QT4	741
TRPM6	TRPV6	Q9H1D0	739
TRPM6	KCNA1	Q09470	733
TRPM6	EGF	P01133	727
TRPM6	TRPC1	P48995	725
TRPM6	FXYD2	P54710	719
TRPM6	CNNM1	Q9NRU3	696
TRPM6	TRPA1	O75762	678

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TRPM6	MYH14	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
TRPM6	MYH10	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MYH9	TRPM6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440

BioGRID (8): TRPM6 (Affinity Capture-MS), TRPM6 (Affinity Capture-MS), TRPM6 (Affinity Capture-MS), TRPM6 (Negative Genetic), TRPM6 (Cross-Linking-MS (XL-MS)), TRPM6 (Cross-Linking-MS (XL-MS)), TRPM6 (Co-fractionation), TRPM6 (Co-fractionation)

ESM2 similar proteins: A0A0R4IMY7, A0JPA0, A2AP18, A8DYE2, J9SQF3, O00329, O35904, O75038, P0C1Q3, P0C588, P19687, P33402, P48736, P97557, Q02108, Q09M05, Q148L1, Q1LWG4, Q2TV84, Q2WEA5, Q3USB7, Q4ZHS0, Q502J0, Q5EBA1, Q60565, Q62688, Q69ZF7, Q6P4Q7, Q6PA06, Q7L5N7, Q7TN37, Q7Z2W7, Q7Z4N2, Q80YD1, Q8BTI9, Q8BYI6, Q8BZN2, Q8CIR4, Q8NHH9, Q8R455

Diamond homologs: A0A0R4IMY7, A7T1N0, A8DYE2, E9PTA2, J9SQF3, O94759, Q09297, Q2TV84, Q2WEA5, Q5XIG0, Q7TN37, Q7Z2W7, Q7Z4N2, Q8BVU5, Q8CIR4, Q8R455, Q8R4D5, Q8TD43, Q91YD4, Q923J1, Q925B3, Q96QT4, Q9BW91, Q9BX84, Q9ESQ5, Q9HCF6, S5UH55, Q93971, O00418, O01991, O08796, P42527, P70531, P90648, Q54DK4, Q54SF9, Q6B9X6, Q8MY12, Q6FLI3, Q96QP1

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RACK1	“down-regulates activity”	TRPM6	binding
TRPM6	“down-regulates activity”	TRPM6	phosphorylation
TRPM6	“down-regulates quantity”	TRPM7	phosphorylation
TRPM6	“down-regulates activity”	H2AC11	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	32
Uncertain significance	506
Likely benign	230
Benign	95

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030275	NM_017662.5(TRPM6):c.841+1G>A	Pathogenic
1064591	NM_017662.5(TRPM6):c.1308+7T>G	Pathogenic
1173100	NM_017662.5(TRPM6):c.4057C>T (p.Arg1353Ter)	Pathogenic
1173101	NM_017662.5(TRPM6):c.3094+2T>C	Pathogenic
1179128	NM_017662.5(TRPM6):c.3694del (p.Gln1232fs)	Pathogenic
1325240	NM_017662.5(TRPM6):c.5314C>T (p.Arg1772Ter)	Pathogenic
1433687	NM_017662.5(TRPM6):c.5567del (p.Pro1856fs)	Pathogenic
1526207	NM_017662.5(TRPM6):c.2782C>T (p.Arg928Ter)	Pathogenic
1705325	NM_017662.5(TRPM6):c.1308+1G>T	Pathogenic
1706553	NM_017662.5(TRPM6):c.1437C>A (p.Tyr479Ter)	Pathogenic
1709626	NM_017662.5(TRPM6):c.3158A>G (p.Tyr1053Cys)	Pathogenic
2081586	NM_017662.5(TRPM6):c.1722C>A (p.Tyr574Ter)	Pathogenic
2097845	NM_017662.5(TRPM6):c.1021delinsAA (p.Pro341fs)	Pathogenic
218238	NM_017662.5(TRPM6):c.2667+1G>A	Pathogenic
2257728	NM_017662.5(TRPM6):c.143del (p.Asn48fs)	Pathogenic
2426340	NC_000009.11:g.(?77397258)(77403678_?)del	Pathogenic
2426341	NC_000009.11:g.(?77358991)(77362850_?)del	Pathogenic
2572474	NM_017662.5(TRPM6):c.3643del (p.Ser1215fs)	Pathogenic
2572490	NM_017662.5(TRPM6):c.2958del (p.Ile986fs)	Pathogenic
2872707	NM_017662.5(TRPM6):c.1282_1283del (p.Ile428fs)	Pathogenic
3245356	NC_000009.11:g.(?77390779)(77397789_?)del	Pathogenic
3575	NM_017662.5(TRPM6):c.1769C>G (p.Ser590Ter)	Pathogenic
3577	NM_017662.5(TRPM6):c.1280del (p.His427fs)	Pathogenic
3578	NM_017662.5(TRPM6):c.3779_3791del (p.Glu1260fs)	Pathogenic
3579	NM_017662.5(TRPM6):c.2208del (p.Arg736fs)	Pathogenic
3580	NM_017662.5(TRPM6):c.2009+1G>A	Pathogenic
3581	NM_017662.5(TRPM6):c.1420C>T (p.Arg474Ter)	Pathogenic
3583	NM_017662.5(TRPM6):c.1010+5G>C	Pathogenic
3584	TRPM6, IVS23AS, A-G, -68	Pathogenic
3585	NM_017662.5(TRPM6):c.422C>T (p.Ser141Leu)	Pathogenic

SpliceAI

7445 predictions. Top by Δscore:

Variant	Effect	Δscore
9:74728233:GCATA:G	donor_loss	1.0000
9:74728234:CATA:C	donor_loss	1.0000
9:74728235:ATACC:A	donor_loss	1.0000
9:74728236:TA:T	donor_loss	1.0000
9:74728237:A:AG	donor_loss	1.0000
9:74728237:AC:A	donor_gain	1.0000
9:74728238:C:A	donor_loss	1.0000
9:74728238:CC:C	donor_gain	1.0000
9:74728346:C:CC	acceptor_gain	1.0000
9:74732683:A:AC	donor_gain	1.0000
9:74732684:C:CC	donor_gain	1.0000
9:74738443:A:AC	donor_gain	1.0000
9:74738444:C:CC	donor_gain	1.0000
9:74738447:A:AC	donor_gain	1.0000
9:74738448:T:C	donor_gain	1.0000
9:74738449:AGGT:A	donor_gain	1.0000
9:74738610:AACC:A	acceptor_loss	1.0000
9:74738611:ACCTG:A	acceptor_loss	1.0000
9:74738612:CCTGT:C	acceptor_loss	1.0000
9:74738613:C:CA	acceptor_loss	1.0000
9:74739362:CTTA:C	donor_loss	1.0000
9:74739364:TA:T	donor_loss	1.0000
9:74739365:ACC:A	donor_loss	1.0000
9:74739366:C:CT	donor_loss	1.0000
9:74747887:A:AC	donor_gain	1.0000
9:74747888:C:CC	donor_gain	1.0000
9:74750662:A:AC	donor_gain	1.0000
9:74750663:C:CC	donor_gain	1.0000
9:74752370:T:C	acceptor_gain	1.0000
9:74752370:T:TC	acceptor_gain	1.0000

AlphaMissense

13406 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:74738569:A:G	W1872R	0.998
9:74738569:A:T	W1872R	0.998
9:74840051:A:G	W173R	0.998
9:74840051:A:T	W173R	0.998
9:74782803:G:C	S990R	0.997
9:74782803:G:T	S990R	0.997
9:74782805:T:G	S990R	0.997
9:74840177:A:G	W131R	0.997
9:74840177:A:T	W131R	0.997
9:74738455:A:G	W1910R	0.996
9:74738455:A:T	W1910R	0.996
9:74782789:C:G	R995P	0.995
9:74739770:A:G	W1814R	0.994
9:74739770:A:T	W1814R	0.994
9:74739938:A:G	W1758R	0.994
9:74739938:A:T	W1758R	0.994
9:74782800:A:C	F991L	0.994
9:74782800:A:T	F991L	0.994
9:74782802:A:G	F991L	0.994
9:74802067:A:G	W614R	0.994
9:74802067:A:T	W614R	0.994
9:74840237:A:C	Y111D	0.994
9:74742580:A:C	F1727L	0.993
9:74742580:A:T	F1727L	0.993
9:74742582:A:G	F1727L	0.993
9:74739798:C:A	K1804N	0.992
9:74739798:C:G	K1804N	0.992
9:74763039:A:G	L1211P	0.992
9:74782380:A:G	L1064P	0.992
9:74782382:G:C	N1063K	0.992

dbSNP variants (sampled 300 via entrez): RS1000002523 (9:74833413 A>G), RS1000006432 (9:74732520 C>T), RS1000027225 (9:74839958 G>A), RS1000031399 (9:74881131 C>T), RS1000034150 (9:74773895 G>A,T), RS1000047178 (9:74861290 A>G), RS1000053990 (9:74793283 T>C), RS1000097386 (9:74746742 A>T), RS1000106148 (9:74785249 T>G), RS1000114386 (9:74853951 A>G), RS1000115199 (9:74833674 C>T), RS1000167427 (9:74864580 G>C), RS1000182800 (9:74771152 G>A), RS1000192229 (9:74770603 G>T), RS1000194446 (9:74736387 A>G)

Disease associations

OMIM: gene MIM:607009 | disease phenotypes: MIM:602014, MIM:600974

GenCC curated gene-disease

Disease	Classification	Inheritance
intestinal hypomagnesemia 1	Strong	Autosomal recessive

Mondo (3): intestinal hypomagnesemia 1 (MONDO:0011176), familial primary hypomagnesemia (MONDO:0018100), autosomal recessive nonsyndromic hearing loss 7 (MONDO:0010967)

Orphanet (3): Primary hypomagnesemia with secondary hypocalcemia (Orphanet:30924), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), OBSOLETE: Genetic primary hypomagnesemia (Orphanet:34526)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001281	Tetany
HP:0002901	Hypocalcemia
HP:0002917	Hypomagnesemia
HP:0003394	Muscle spasm
HP:0003593	Infantile onset

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000756_8	Magnesium levels	8.000000e-15
GCST002933_3	Magnesium levels	5.000000e-07
GCST005124_2	Urinary magnesium-to-creatinine ratio	4.000000e-13
GCST006923_14	Loneliness	5.000000e-09
GCST006924_6	Loneliness (MTAG)	2.000000e-09
GCST007830_3	Anti-thyroid peroxidase (TPOAb) levels in Hashimoto’s thyroiditis	1.000000e-06
GCST007851_6	Anti-thyroid peroxidase (TPOAb) and anti-thyroglobulin (TgAb) levels in Hashimoto’s thyroiditis	5.000000e-06
GCST008642_2	Annualised percent change of cerebrospinal fluid AB1-42 levels	2.000000e-06
GCST008758_4	Pre-treatment viral load in HIV-1 infection	4.000000e-16
GCST009313_8	Prepulse inhibition of the startle response	6.000000e-06
GCST009391_1119	Metabolite levels	2.000000e-06
GCST009391_1806	Metabolite levels	8.000000e-06
GCST009391_842	Metabolite levels	2.000000e-06
GCST012490_124	Femur bone mineral density x serum urate levels interaction	1.000000e-08
GCST012490_228	Femur bone mineral density x serum urate levels interaction	3.000000e-10

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004845	magnesium measurement
EFO:0008449	magnesium:creatinine ratio measurement
EFO:0007865	loneliness measurement
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0010125	viral load
EFO:0007969	cognitive inhibition measurement
EFO:0010523	phosphoglyceric acid measurement
EFO:0010403	triacylglycerol 48:0 measurement
EFO:0010400	triacylglycerol 46:0 measurement
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C563417	Deafness, Autosomal Recessive 7 (supp.)
C566593	Hypomagnesemia 1, Intestinal (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1628470 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 11,912 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL230011	TG100-115	2	1,504

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3750425	TRPM6		0.00	0
rs2274924	TRPM6		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — ChaK subfamily

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
Ca2+	Channel blocker	5.32	pIC50
2-APB	Agonist	3.7	pEC50

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.10	Kd	7.9	nM	TG100-115
5.16	Kd	7000	nM	TOFACITINIB

PubChem BioAssay actives

2 with measured affinity, of 106 total; 2 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
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	625110: Binding constant for TRPM6 kinase domain	kd	0.0079	uM
Tofacitinib	2116008: Binding affinity to TRPM6 (unknown origin) assessed as dissociation constant	kd	7.0000	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
1-oleoyl-2-acetylglycerol	affects reaction, decreases reaction, increases transport	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
1-stearoyl-2-arachidonoylglycerol	affects reaction, increases transport	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Amphotericin B	increases expression	1
Barium	affects reaction, increases transport	1
Benzo(a)pyrene	decreases methylation	1
Calcium	affects reaction, decreases reaction, increases transport	1
Gadolinium	affects reaction, decreases reaction, increases transport	1
Lanthanum	affects reaction, decreases reaction, increases transport	1
Methotrexate	decreases expression	1
Silicon Dioxide	increases expression	1
Strontium	affects reaction, increases transport	1
Vitamin E	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

56 unique, capped per target: 55 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1175107	Binding	Inhibition of TRPM6 at 10 uM	Broad spectrum alkynyl inhibitors of T315I Bcr-Abl. — Bioorg Med Chem Lett
CHEMBL3734575	Functional	Inhibition of TRPM6 (unknown origin) expressed in HEK293 cells assessed as effect on agonist-induced Ca2+ changes	Agents and methods for treating ischemic and other diseases

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8D5	Ubigene A-549 TRPM6 KO	Cancer cell line	Male
CVCL_E0SA	Ubigene HeLa TRPM6 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00603499	PHASE4	COMPLETED	Magnesium and Metabolic Syndrome
NCT00994006	PHASE4	COMPLETED	The Absorption of Magnesium Oxide Compared to Citrate in Healthy Subjects
NCT03088852	PHASE4	RECRUITING	Magnesium Deficiency In Patients Hospitalized in Internal Medicine Wards
NCT03812380	PHASE3	TERMINATED	Averting Complications of Proton Pump Inhibitor Therapy by Effervescent Calcium Magnesium Citrate
NCT05998863	PHASE3	RECRUITING	EffCaMgCit to Prevent Mineral Metabolism and Renal Complications of Chronic PPI Therapy
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT02216877	PHASE1/PHASE2	COMPLETED	Magnesium Supplementation for Hypomagnesemia in Chronic Kidney Disease
NCT04382157	PHASE1/PHASE2	UNKNOWN	Magnesium Replacement and Hyperglycemia After Kidney Transplantation
NCT01700998	Not specified	COMPLETED	Magnesium Replacement Therapy to Prevent Acute Renal Failure in Critically Ill Patients
NCT02690012	Not specified	COMPLETED	Feasibility of Using an Integrated Consent Model to Compare Two Standard of Care Regimens for the Management of Hypomagnesemia From Anti-Cancer Therapies
NCT03976440	Not specified	UNKNOWN	Simplified Regional Citrate Anticoagulation Protocols for CVVH, CVVHDF and SLED: a Pilot Study
NCT04351451	Not specified	COMPLETED	Hypomagnesemia and Hypocalcemia Association Following Thyroidectomy
NCT04426994	Not specified	COMPLETED	Hypomagnesemia Associated With Proton-Pump Inhibitor Use
NCT06353750	Not specified	UNKNOWN	Intracellular Magnesium and Heart Failure
NCT06855550	Not specified	COMPLETED	Postoperative Incidence of Atrial Fibrillation Following Cardiac Surgery
NCT07056283	Not specified	RECRUITING	The Study of Urinary Biomarkers in Patients With Hypomagnesemia
NCT07089004	Not specified	COMPLETED	Hypomagnesemia and Its Clinical Outcome
NCT07380542	Not specified	COMPLETED	Dynamic Magnesium Replacement Strategies and 28-Day Mortality in Non-Cardiac Critically Ill Patients With Hypomagnesemia: A Target Trial Emulation
NCT07576621	Not specified	COMPLETED	Association Between Hypomagnesemia and Coagulopathy in Sepsis