CNNM2

Summary

CNNM2 (cyclin and CBS domain divalent metal cation transport mediator 2, HGNC:103) is a protein-coding gene on chromosome 10q24.32, encoding Metal transporter CNNM2 (Q9H8M5). Divalent metal cation transporter.

This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play an important role in magnesium homeostasis by mediating the epithelial transport and renal reabsorption of Mg2+. Mutations in this gene are associated with renal hypomagnesemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 54805 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypomagnesemia, seizures, and intellectual disability 1 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 61
• Clinical variants (ClinVar): 534 total — 24 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 19
• MANE Select transcript: NM_017649

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:103
Approved symbol	CNNM2
Name	cyclin and CBS domain divalent metal cation transport mediator 2
Location	10q24.32
Locus type	gene with protein product
Status	Approved
Aliases	SLC70A2
Ensembl gene	ENSG00000148842
Ensembl biotype	protein_coding
OMIM	607803
Entrez	54805

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000369875, ENST00000369878, ENST00000433628, ENST00000475511, ENST00000970832

RefSeq mRNA: 3 — MANE Select: NM_017649 NM_017649, NM_199076, NM_199077

CCDS: CCDS44474, CCDS44475, CCDS7543

Canonical transcript exons

ENST00000369878 — 8 exons

Exon	Start	End
ENSE00000987732	103068629	103068722
ENSE00001025936	103071774	103071839
ENSE00001288096	103076971	103090222
ENSE00001661582	103054329	103054466
ENSE00001788039	102918294	102920101
ENSE00001806333	103056795	103056964
ENSE00002517953	103049707	103049850
ENSE00003490174	103076086	103076270

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 96.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1725 / max 212.0592, expressed in 1631 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106778	4.9816	1588
106779	1.1737	472
106782	0.0173	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	96.63	gold quality
oocyte	CL:0000023	93.03	gold quality
right adrenal gland	UBERON:0001233	82.35	gold quality
sural nerve	UBERON:0015488	82.24	gold quality
right adrenal gland cortex	UBERON:0035827	82.17	gold quality
choroid plexus epithelium	UBERON:0003911	82.13	gold quality
left adrenal gland	UBERON:0001234	81.98	gold quality
left adrenal gland cortex	UBERON:0035825	81.51	gold quality
popliteal artery	UBERON:0002250	81.15	gold quality
tibial artery	UBERON:0007610	81.11	gold quality
middle temporal gyrus	UBERON:0002771	80.99	silver quality
adrenal gland	UBERON:0002369	80.66	gold quality
adrenal cortex	UBERON:0001235	80.29	gold quality
endothelial cell	CL:0000115	80.26	silver quality
mucosa of transverse colon	UBERON:0004991	80.03	gold quality
pancreatic ductal cell	CL:0002079	79.88	silver quality
islet of Langerhans	UBERON:0000006	79.39	gold quality
Brodmann (1909) area 23	UBERON:0013554	79.19	gold quality
adrenal tissue	UBERON:0018303	78.97	gold quality
aorta	UBERON:0000947	78.82	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.43	silver quality
primary visual cortex	UBERON:0002436	78.02	gold quality
left coronary artery	UBERON:0001626	77.87	gold quality
medial globus pallidus	UBERON:0002477	77.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.36	gold quality
cortical plate	UBERON:0005343	77.29	gold quality
ventricular zone	UBERON:0003053	77.17	gold quality
coronary artery	UBERON:0001621	77.07	gold quality
stromal cell of endometrium	CL:0002255	76.95	gold quality
prefrontal cortex	UBERON:0000451	76.74	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	2492.31
E-GEOD-131882	yes	2451.07
E-ANND-3	no	6.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

88 targeting CNNM2, 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-9-5P	100.00	72.28	2361
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-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4779	99.86	66.50	1583

Literature-anchored findings (GeneRIF, showing 18)

• ACDP2 splice-variant 1 is a functional Mg2+-transporting entity per se. (PMID:20519162)
• The CNNM2 locus is associated with serum Mg(2+) concentrations. (PMID:21397062)
• analysis of structure of CNNM2 and its post-translational modifications (PMID:22399287)
• crystals of CNNM2 belonged to space groups P2(1)2(1)2 and I222 (or I2(1)2(1)2(1)) and diffracted X-rays to 2.0 and 3.6 A resolution, respectively, using synchrotron radiation (PMID:23027747)
• Our findings suggest that the genetic variant in the CNNM2 gene could be implicated in the pathogenesis of schizophrenia through the gray matter volumetric vulnerability of the orbital regions in the inferior frontal gyri. (PMID:24160291)
• This CNNM2 risk variant rs7914558 may have an impact on neural systems relevant to social cognition. (PMID:24311551)
• Cells expressing mutated CNNM2 proteins did not show increased Mg(2+) uptake. (PMID:24699222)
• meta-analysis of two Caucasian cohorts did not show an association between five aneurysm associated loci and sporadic brain Arteriovenous malformations. (PMID:25053769)
• The T568I mutation causes the magnesium transporter, CNNM2, to become ’locked’ in its flat form. (PMID:25184538)
• this study implicates altered neural expression of BORCS7, AS3MT, and NT5C2 in susceptibility to schizophrenia arising from genetic variation at the chromosome 10q24 locus (PMID:27004590)
• Sensitivity of CNNM2 expression to extracellular Mg(2+) depletion depends on cell type. (PMID:27068403)
• In this large-scale, Han Chinese population-based genetic association study for genetic susceptibility to schizophrenia of a three-gene cluster region, AS3MT-CNNM2-NT5C2, two SNPs with independent effects, rs11191419 and rs11191514, were identified. Rs11191419 is located on the 5’ (potential promoter) region of AS3MT, while rs11191514 is located in one of the introns of CNNM2. (PMID:27401531)
• CNNM2 single nucleotide polymorphisms association with the risk of hypertension in Chinese Han population. (PMID:30180964)
• This study determined the first crystal structures of the cyclic nucleotide-binding homology (CNBH) domain domains of CNNM2 and CNNM3 at 2.6 and 1.9 A resolutions. (PMID:30341174)
• Novel variant in the CNNM2 gene associated with dominant hypomagnesemia. (PMID:32997713)
• The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2). (PMID:33600043)
• Decreased CNNM2 expression in prefrontal cortex affects sensorimotor gating function, cognition, dendritic spine morphogenesis and risk of schizophrenia. (PMID:37715107)
• Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants. (PMID:38519529)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnnm2a	ENSDARG00000061195
danio_rerio	cnnm2b	ENSDARG00000078733
mus_musculus	Cnnm2	ENSMUSG00000064105
rattus_norvegicus	Cnnm2	ENSRNOG00000020113
drosophila_melanogaster	uex	FBGN0262124
caenorhabditis_elegans		WBGENE00011260
caenorhabditis_elegans		WBGENE00016343
caenorhabditis_elegans		WBGENE00016879

Paralogs (3): CNNM1 (ENSG00000119946), CNNM4 (ENSG00000158158), CNNM3 (ENSG00000168763)

Protein

Protein identifiers

Metal transporter CNNM2 — Q9H8M5 (reviewed: Q9H8M5)

Alternative names: Ancient conserved domain-containing protein 2, Cyclin-M2

All UniProt accessions (1): Q9H8M5

UniProt curated annotations — full annotation on UniProt →

Function. Divalent metal cation transporter. Mediates transport of divalent metal cations in an order of Mg(2+) > Co(2+) > Mn(2+) > Sr(2+) > Ba(2+) > Cu(2+) > Fe(2+).

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed. Expressed at higher level in brain, kidney and placenta, while it is weakly expressed in skeletal muscle. In the kidney, it is expressed in the distal convoluted tubule and the thick ascending limb of Henle loop.

Disease relevance. Hypomagnesemia 6 (HOMG6) [MIM:613882] A renal disease characterized by severely lowered serum magnesium levels in the absence of other electrolyte disturbances. Affected individuals show an inappropriately normal urinary magnesium excretion, demonstrating a defect in tubular reabsorption. Age of clinical onset is highly variable and some affected individuals are asymptomatic. The disease is caused by variants affecting the gene represented in this entry. Hypomagnesemia, seizures, and impaired intellectual development 1 (HOMGSMR1) [MIM:616418] A disease characterized by renal wasting of magnesium, low serum magnesium, seizures, and variable degrees of delayed psychomotor development. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Shares weak sequence similarity with the cyclin family, hence its name. However, it has no cyclin-like function in vivo.

Similarity. Belongs to the ACDP family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H8M5-1	1	yes
Q9H8M5-2	2
Q9H8M5-3	3

RefSeq proteins (3): NP_060119, NP_951058, NP_951059 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000644	CBS_dom	Domain
IPR002550	CNNM	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR044751	Ion_transp-like_CBS	Domain
IPR045095	ACDP	Family
IPR046342	CBS_dom_sf	Homologous_superfamily
IPR057492	Ig_CNNM1/2/4_N	Domain

Pfam: PF00571, PF01595, PF25511, PF25562

UniProt features (67 total): strand 17, helix 15, sequence variant 6, turn 6, topological domain 5, domain 3, splice variant 3, transmembrane region 3, sequence conflict 3, region of interest 2, chain 1, modified residue 1, glycosylation site 1, intramembrane region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4IYS	X-RAY DIFFRACTION	1.8
4IY0	X-RAY DIFFRACTION	1.9
6DJ3	X-RAY DIFFRACTION	2.6
4IY4	X-RAY DIFFRACTION	2.9
8F6D	X-RAY DIFFRACTION	3.2
6N7E	X-RAY DIFFRACTION	3.5
4IY2	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H8M5-F1	71.70	0.29

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 (1): 761

Glycosylation sites (1): 112

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 174 (showing top): BENPORATH_ES_WITH_H3K27ME3, NKX25_02, AP4_Q6, GOBP_MAGNESIUM_ION_TRANSPORT, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, MCAATNNNNNGCG_UNKNOWN, MYOD_01, GOBP_MONOATOMIC_ION_HOMEOSTASIS, SABATES_COLORECTAL_ADENOMA_DN, E12_Q6, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, GOBP_TRANSMEMBRANE_TRANSPORT, PARENT_MTOR_SIGNALING_UP, GOBP_HOMEOSTATIC_PROCESS

GO Biological Process (4): magnesium ion homeostasis (GO:0010960), monoatomic ion transport (GO:0006811), magnesium ion transport (GO:0015693), magnesium ion transmembrane transport (GO:1903830)

GO Molecular Function (2): ATP binding (GO:0005524), magnesium ion transmembrane transporter activity (GO:0015095)

GO Cellular Component (5): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), glutamatergic synapse (GO:0098978), membrane (GO:0016020), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
transport	1
metal ion transport	1
magnesium ion transport	1
monoatomic cation transmembrane transport	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
metal ion transmembrane transporter activity	1
magnesium ion transmembrane transport	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
synapse	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1132 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNNM2	H7C2H4	H7C2H4	810
CNNM2	NT5C2	P49902	790
CNNM2	SLC41A1	Q8IVJ1	789
CNNM2	P0DN79	P0DN79	785
CNNM2	TRPM6	Q9BX84	780
CNNM2	STARD13	Q9Y3M8	765
CNNM2	NIPAL1	Q6NVV3	741
CNNM2	AS3MT	Q9HBK9	690
CNNM2	SLC41A3	Q96GZ6	688
CNNM2	SLC41A2	Q96JW4	671
CNNM2	CLDN16	Q9Y5I7	647
CNNM2	TRPM7	Q96QT4	637
CNNM2	FBN2	P35556	631
CNNM2	RBBP8	Q99708	624
CNNM2	NIPAL3	Q6P499	619

IntAct

42 interactions, top by confidence:

A	B	Type	Score
PTP4A1	CNNM4	psi-mi:“MI:0914”(association)	0.740
PTP4A2	CNNM4	psi-mi:“MI:0914”(association)	0.740
PTP4A2	PTP4A3	psi-mi:“MI:0914”(association)	0.640
ARL15	SLC25A20	psi-mi:“MI:0914”(association)	0.530
PTP4A1	ATE1	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
GALNS	CLGN	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
PTP4A1	PSMD3	psi-mi:“MI:0914”(association)	0.420
PTP4A2	USP11	psi-mi:“MI:2364”(proximity)	0.420
PTP4A1	PSMD3	psi-mi:“MI:2364”(proximity)	0.420
M	TM9SF1	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
BTNL8	TMEM131L	psi-mi:“MI:0914”(association)	0.350
CLEC2D	ESYT2	psi-mi:“MI:0914”(association)	0.350
DIO3	BLTP3B	psi-mi:“MI:0914”(association)	0.350
UPK2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
GP5	MGST3	psi-mi:“MI:0914”(association)	0.350
ICAM2	RAB29	psi-mi:“MI:0914”(association)	0.350
ARL15	OXSR1	psi-mi:“MI:0914”(association)	0.350
ARL15	NDUFS6	psi-mi:“MI:0914”(association)	0.350
C1orf54	QSOX1	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PTP4A1	NME6	psi-mi:“MI:0914”(association)	0.350

BioGRID (56): CNNM2 (Affinity Capture-MS), CNNM2 (Proximity Label-MS), CNNM2 (Affinity Capture-MS), CNNM2 (Affinity Capture-MS), CNNM2 (Affinity Capture-MS), CNNM2 (Affinity Capture-RNA), CNNM2 (Affinity Capture-MS), CNNM2 (Affinity Capture-MS), CNNM2 (Proximity Label-MS), CNNM2 (Proximity Label-MS), CNNM2 (Affinity Capture-RNA), CNNM2 (Affinity Capture-MS), CNNM2 (Affinity Capture-MS), CNNM2 (Proximity Label-MS), CNNM2 (Proximity Label-MS)

ESM2 similar proteins: A0A0B7P9G0, A0A0R4IMY7, A0JPA0, D3ZAA9, O35454, P0C1Q3, P0C588, P16067, P20594, P32232, P33402, P35525, P46197, P47823, P51432, P51788, Q01970, Q13144, Q14168, Q1LWG4, Q32PX9, Q3TWN3, Q3USB7, Q3V384, Q4U2V3, Q502J0, Q5EBA1, Q5U2P1, Q62688, Q66K14, Q69ZF7, Q6P4Q7, Q7L5N7, Q80YD1, Q8BYI6, Q8CIR4, Q8IYB8, Q8K394, Q8WV93, Q91WT9

Diamond homologs: A0A0B7P9G0, A0A131MCZ8, A0JPA0, A3QM97, A8EZU0, A8F2M1, A8GPR9, A8GTI4, A8GUH1, O05961, P0C588, Q0GA42, Q12296, Q1RGX2, Q32NY4, Q3TWN3, Q4UK99, Q4V3C7, Q54318, Q57368, Q5U2P1, Q67XQ0, Q68W10, Q69ZF7, Q6P4Q7, Q8NE01, Q8RY60, Q8VZI2, Q92GI2, Q9GYL2, Q9H8M5, Q9LTD8, Q9NRU3, Q9USJ3, Q9ZQR4, Q9ZVS8, Q9CM13, Q9LK65, O05241, O07585

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	18
Uncertain significance	275
Likely benign	141
Benign	39

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013600	NM_017649.5(CNNM2):c.1147A>G (p.Met383Val)	Pathogenic
1685993	NM_001351169.2(NT5C2):c.1624del (p.Gln542fs)	Pathogenic
192323	NM_017649.5(CNNM2):c.364G>A (p.Glu122Lys)	Pathogenic
192324	NM_017649.5(CNNM2):c.1069G>A (p.Glu357Lys)	Pathogenic
2024104	NM_017649.5(CNNM2):c.1601del (p.Met534fs)	Pathogenic
2578368	NM_017649.5(CNNM2):c.274G>C (p.Ala92Pro)	Pathogenic
2578372	NM_017649.5(CNNM2):c.970G>C (p.Val324Leu)	Pathogenic
2578374	NM_017649.5(CNNM2):c.1291G>A (p.Glu431Lys)	Pathogenic
2578375	NM_017649.5(CNNM2):c.1310G>A (p.Gly437Glu)	Pathogenic
2578376	NM_017649.5(CNNM2):c.2384C>A (p.Ser795Ter)	Pathogenic
2864063	NM_017649.5(CNNM2):c.12T>A (p.Cys4Ter)	Pathogenic
30683	NM_017649.5(CNNM2):c.117del (p.Ile40fs)	Pathogenic
30684	NM_017649.5(CNNM2):c.1703C>T (p.Thr568Ile)	Pathogenic
3339041	NM_017649.5(CNNM2):c.1936del (p.Glu646fs)	Pathogenic
3652451	NM_017649.5(CNNM2):c.274del (p.Ala92fs)	Pathogenic
4731665	NM_017649.5(CNNM2):c.318C>A (p.Tyr106Ter)	Pathogenic
642627	NC_000010.11:g.(?103089662)(103174968_?)del	Pathogenic
996041	NM_017649.5(CNNM2):c.143T>C (p.Leu48Pro)	Pathogenic
996042	NM_017649.5(CNNM2):c.942C>G (p.Tyr314Ter)	Pathogenic
996043	NM_017649.5(CNNM2):c.955CTG[2] (p.Leu321del)	Pathogenic
996044	NM_017649.5(CNNM2):c.970G>A (p.Val324Met)	Pathogenic
996045	NM_017649.5(CNNM2):c.1253T>C (p.Leu418Pro)	Pathogenic
996052	NC_000010.10:g.(?104678237)(104816721_?)del	Pathogenic
996053	NM_017649.5(CNNM2):c.1842_1844del (p.Ser614_Glu615delinsArg)	Pathogenic
1098410	NM_017649.5(CNNM2):c.1804C>T (p.Arg602Ter)	Likely pathogenic
1342906	NM_017649.5(CNNM2):c.312_315dup (p.Tyr106fs)	Likely pathogenic
1696568	NM_017649.5(CNNM2):c.522dup (p.Ile175fs)	Likely pathogenic
1709797	NM_017649.5(CNNM2):c.992C>T (p.Thr331Ile)	Likely pathogenic
2578373	NM_017649.5(CNNM2):c.1003G>A (p.Asp335Asn)	Likely pathogenic
2581787	NM_017649.5(CNNM2):c.980A>G (p.Asn327Ser)	Likely pathogenic

SpliceAI

2913 predictions. Top by Δscore:

Variant	Effect	Δscore
10:102921003:ACCTT:A	acceptor_gain	1.0000
10:102921007:T:A	acceptor_gain	1.0000
10:103049702:TAAA:T	acceptor_loss	1.0000
10:103049703:A:AG	acceptor_gain	1.0000
10:103049703:AAAG:A	acceptor_gain	1.0000
10:103049704:A:G	acceptor_gain	1.0000
10:103049706:GGT:G	acceptor_gain	1.0000
10:103049706:GGTA:G	acceptor_gain	1.0000
10:103049706:GGTAA:G	acceptor_gain	1.0000
10:103049846:ATACA:A	donor_gain	1.0000
10:103049847:TACA:T	donor_gain	1.0000
10:103049848:ACA:A	donor_gain	1.0000
10:103049849:CA:C	donor_gain	1.0000
10:103049850:AGT:A	donor_loss	1.0000
10:103049851:G:GG	donor_gain	1.0000
10:103054315:A:AG	acceptor_gain	1.0000
10:103054327:A:AG	acceptor_gain	1.0000
10:103054328:G:GA	acceptor_gain	1.0000
10:103054328:GCT:G	acceptor_gain	1.0000
10:103056793:A:AG	acceptor_gain	1.0000
10:103056794:G:GC	acceptor_gain	1.0000
10:103056794:GAA:G	acceptor_gain	1.0000
10:103056962:CAG:C	donor_loss	1.0000
10:103056963:AG:A	donor_loss	1.0000
10:103056965:G:C	donor_loss	1.0000
10:103056966:T:G	donor_loss	1.0000
10:103068623:CCACA:C	acceptor_loss	1.0000
10:103068624:CACAG:C	acceptor_loss	1.0000
10:103068627:A:AC	acceptor_loss	1.0000
10:103068627:AGGG:A	acceptor_gain	1.0000

AlphaMissense

5706 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:102918706:G:A	G76R	1.000
10:102918706:G:C	G76R	1.000
10:102918706:G:T	G76W	1.000
10:102918707:G:A	G76E	1.000
10:102918710:T:C	L77P	1.000
10:102918788:T:C	L103P	1.000
10:102918791:G:C	R104P	1.000
10:102918799:G:A	G107R	1.000
10:102918799:G:C	G107R	1.000
10:102918799:G:T	G107W	1.000
10:102918800:G:A	G107E	1.000
10:102918800:G:T	G107V	1.000
10:102918838:T:C	F120L	1.000
10:102918839:T:C	F120S	1.000
10:102918839:T:G	F120C	1.000
10:102918840:C:A	F120L	1.000
10:102918840:C:G	F120L	1.000
10:102918928:T:A	C150S	1.000
10:102918928:T:C	C150R	1.000
10:102918929:G:A	C150Y	1.000
10:102918929:G:C	C150S	1.000
10:102918947:A:G	D156G	1.000
10:102918947:A:T	D156V	1.000
10:102918988:T:C	S170P	1.000
10:102918992:G:A	G171D	1.000
10:102919054:T:A	C192S	1.000
10:102919054:T:C	C192R	1.000
10:102919055:G:A	C192Y	1.000
10:102919055:G:C	C192S	1.000
10:102919056:C:G	C192W	1.000

dbSNP variants (sampled 300 via entrez): RS1000011984 (10:103025974 C>G,T), RS1000017527 (10:103007828 C>T), RS1000022232 (10:103012032 A>C,G,T), RS1000038161 (10:103073436 G>A,T), RS1000049282 (10:103054209 C>T), RS1000052820 (10:103048020 C>A), RS1000065237 (10:103055870 G>A,C), RS1000090410 (10:102964339 C>T), RS1000134082 (10:102920777 T>C), RS1000141423 (10:102963988 C>CT), RS1000143073 (10:102940878 C>A,G,T), RS1000146454 (10:102985008 T>C), RS1000166323 (10:102943436 A>G), RS1000170125 (10:102988456 G>A,C), RS1000182503 (10:103032144 C>A)

Disease associations

OMIM: gene MIM:607803 | disease phenotypes: MIM:602014, MIM:613162, MIM:303350, MIM:613882, MIM:616418

GenCC curated gene-disease

Disease	Classification	Inheritance
hypomagnesemia, seizures, and intellectual disability 1	Definitive	Semidominant
renal hypomagnesemia 6	Strong	Autosomal dominant
familial primary hypomagnesemia with normocalciuria and normocalcemia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hypomagnesemia, seizures, and intellectual disability 1	Definitive	SD

Mondo (7): familial primary hypomagnesemia (MONDO:0018100), hereditary spastic paraplegia 45 (MONDO:0013165), hereditary spastic paraplegia (MONDO:0019064), renal hypomagnesemia 6 (MONDO:0013480), hypomagnesemia, seizures, and intellectual disability 1 (MONDO:0020787), intellectual disability (MONDO:0001071), familial primary hypomagnesemia with normocalciuria and normocalcemia (MONDO:0018101)

Orphanet (6): Autosomal recessive spastic paraplegia type 45 (Orphanet:320396), Hereditary spastic paraplegia (Orphanet:685), OBSOLETE: Familial primary hypomagnesemia with normocalciuria and normocalcemia (Orphanet:34527), Moyamoya angiopathy (Orphanet:477768), OBSOLETE: Genetic primary hypomagnesemia (Orphanet:34526), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0002315	Headache
HP:0002321	Vertigo
HP:0002917	Hypomagnesemia
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0011463	Childhood onset
HP:0025501	Class III obesity
HP:0025708	Early young adult onset
HP:0033759	Impaired renal tubular reabsorption of magnesium
HP:0100954	Open operculum

GWAS associations

61 associations (top):

Study	Trait	p-value
GCST000395_3	Systolic blood pressure	7.000000e-24
GCST000528_8	Parkinson’s disease	7.000000e-08
GCST000646_4	Intracranial aneurysm	1.000000e-09
GCST000998_10	Coronary heart disease	1.000000e-09
GCST001072_2	Blood pressure	4.000000e-17
GCST001074_8	Blood pressure	7.000000e-12
GCST001242_16	Schizophrenia	2.000000e-08
GCST001421_2	Arsenic metabolism	3.000000e-08
GCST001565_4	Schizophrenia	2.000000e-09
GCST001851_9	Schizophrenia	3.000000e-07
GCST001877_30	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	2.000000e-09
GCST001942_1	Prostate cancer	5.000000e-10
GCST002149_2	Schizophrenia	4.000000e-13
GCST002289_22	Coronary artery disease	1.000000e-06
GCST002290_15	Coronary artery disease or large artery stroke	2.000000e-08
GCST002539_4	Schizophrenia	6.000000e-19
GCST003116_37	Coronary artery disease	5.000000e-09
GCST003117_1	Myocardial infarction	8.000000e-08
GCST003151_2	White matter lesion progression	1.000000e-06
GCST003253_11	Microalbuminuria	6.000000e-06
GCST004521_172	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_78	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST004602_188	Mean corpuscular volume	5.000000e-17
GCST004622_32	Reticulocyte count	1.000000e-51
GCST004630_243	Mean corpuscular hemoglobin	2.000000e-21
GCST004787_23	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	6.000000e-09
GCST004946_86	Schizophrenia	4.000000e-20
GCST005194_169	Coronary artery disease	2.000000e-12
GCST005956_50	Waist-to-hip ratio adjusted for BMI	8.000000e-06
GCST005958_15	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0004880	urinary arsenic measurement
EFO:0007746	white matter lesion progression measurement
EFO:0007986	reticulocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004534	creatine kinase measurement
EFO:0006340	mean arterial pressure
EFO:0005670	smoking initiation
EFO:0005763	pulse pressure measurement
EFO:0009863	anxiety measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0007820	cognitive behavioural therapy
EFO:0004346	neuroimaging measurement
EFO:0004528	mean corpuscular hemoglobin concentration

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11191548	CNNM2		0.00	0
rs3740387	CNNM2, NT5C2		0.00	0
rs58700372	CNNM2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	5
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol A	increases expression	1
titanium dioxide	decreases methylation	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases abundance, increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Dasatinib	increases expression	1
Irinotecan	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression	1
Amiodarone	increases expression	1
Arsenic	increases abundance, increases expression	1
Azacitidine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	increases phosphorylation	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects expression	1

Clinical trials (associated diseases)

267 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
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
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
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)