CNNM3

Summary

CNNM3 (cyclin and CBS domain divalent metal cation transport mediator 3, HGNC:104) is a protein-coding gene on chromosome 2q11.2, encoding Metal transporter CNNM3 (Q8NE01). Probable metal transporter.

Predicted to enable transmembrane transporter activity. Predicted to be involved in magnesium ion homeostasis. Located in membrane.

Source: NCBI Gene 26505 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 153 total
• MANE Select transcript: NM_017623

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:104
Approved symbol	CNNM3
Name	cyclin and CBS domain divalent metal cation transport mediator 3
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	SLC70A3
Ensembl gene	ENSG00000168763
Ensembl biotype	protein_coding
OMIM	607804
Entrez	26505

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000305510, ENST00000377060, ENST00000465224, ENST00000480035, ENST00000494595, ENST00000867797, ENST00000947262, ENST00000947263, ENST00000947264, ENST00000947265

RefSeq mRNA: 2 — MANE Select: NM_017623 NM_017623, NM_199078

CCDS: CCDS2025, CCDS2026

Canonical transcript exons

ENST00000305510 — 8 exons

Exon	Start	End
ENSE00001160895	96828567	96828700
ENSE00001160902	96828099	96828195
ENSE00001160909	96827731	96827900
ENSE00001160920	96825058	96825201
ENSE00001853337	96816268	96817502
ENSE00003520896	96828996	96829134
ENSE00003530570	96826833	96826982
ENSE00003844105	96832552	96835382

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 95.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.0165 / max 63.2175, expressed in 1683 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21490	7.6482	1680
21492	0.3683	215

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	95.34	gold quality
muscle of leg	UBERON:0001383	94.68	gold quality
cerebellar hemisphere	UBERON:0002245	94.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.39	gold quality
cerebellar cortex	UBERON:0002129	94.26	gold quality
right uterine tube	UBERON:0001302	94.19	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.18	gold quality
cerebellum	UBERON:0002037	93.44	gold quality
ventricular zone	UBERON:0003053	92.82	gold quality
cardia of stomach	UBERON:0001162	91.16	gold quality
pylorus	UBERON:0001166	91.12	gold quality
body of pancreas	UBERON:0001150	91.10	gold quality
sural nerve	UBERON:0015488	90.55	gold quality
left ovary	UBERON:0002119	90.22	gold quality
body of uterus	UBERON:0009853	90.16	gold quality
tibial nerve	UBERON:0001323	90.11	gold quality
nipple	UBERON:0002030	89.93	gold quality
right lobe of liver	UBERON:0001114	89.92	gold quality
right ovary	UBERON:0002118	89.72	gold quality
fundus of stomach	UBERON:0001160	89.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.50	gold quality
pancreas	UBERON:0001264	88.97	gold quality
ganglionic eminence	UBERON:0004023	88.88	gold quality
mucosa of stomach	UBERON:0001199	88.84	gold quality
islet of Langerhans	UBERON:0000006	88.83	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.80	gold quality
pituitary gland	UBERON:0000007	88.68	gold quality
endocervix	UBERON:0000458	88.62	gold quality
cortical plate	UBERON:0005343	88.53	gold quality
body of stomach	UBERON:0001161	88.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	240.85
E-ANND-3	yes	8.78
E-MTAB-6142	no	36.50

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

150 targeting CNNM3, 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-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3613-3P	100.00	76.36	7965
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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-185-3P	99.95	67.01	1743

Literature-anchored findings (GeneRIF, showing 4)

• 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)
• A FRET-based screening method to detect potential inhibitors of the binding of CNNM3 to PRL2. (PMID:32733084)
• CNN3 in glioma: The prognostic factor and a potential immunotherapeutic target. (PMID:34797350)
• CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. (PMID:34928937)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000099568
mus_musculus	Cnnm3	ENSMUSG00000001138
rattus_norvegicus	Cnnm3	ENSRNOG00000016032
drosophila_melanogaster	uex	FBGN0262124
caenorhabditis_elegans		WBGENE00011260
caenorhabditis_elegans		WBGENE00016343
caenorhabditis_elegans		WBGENE00016879

Paralogs (3): CNNM1 (ENSG00000119946), CNNM2 (ENSG00000148842), CNNM4 (ENSG00000158158)

Protein

Protein identifiers

Metal transporter CNNM3 — Q8NE01 (reviewed: Q8NE01)

Alternative names: Ancient conserved domain-containing protein 3, Cyclin-M3

All UniProt accessions (1): Q8NE01

UniProt curated annotations — full annotation on UniProt →

Function. Probable metal transporter.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed. Expressed at higher level in heart and spleen.

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?
Q8NE01-1	1	yes
Q8NE01-2	2
Q8NE01-3	3

RefSeq proteins (2): NP_060093, NP_951060 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000644	CBS_dom	Domain
IPR002550	CNNM	Domain
IPR044751	Ion_transp-like_CBS	Domain
IPR045095	ACDP	Family
IPR046342	CBS_dom_sf	Homologous_superfamily

Pfam: PF00571, PF25562

UniProt features (57 total): strand 16, helix 14, sequence conflict 7, turn 5, transmembrane region 4, domain 3, modified residue 2, splice variant 2, chain 1, glycosylation site 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6DFD	X-RAY DIFFRACTION	1.9
6WUR	X-RAY DIFFRACTION	2.88
5K23	X-RAY DIFFRACTION	2.96
5K22	X-RAY DIFFRACTION	3
5K25	X-RAY DIFFRACTION	3.05
5TSR	X-RAY DIFFRACTION	3.19
6MN6	X-RAY DIFFRACTION	3.36

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NE01-F1	67.63	0.19

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 (2): 661, 700

Glycosylation sites (1): 73

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 116 (showing top): FISCHER_G1_S_CELL_CYCLE, FOXO1_01, WANG_RESPONSE_TO_BEXAROTENE_UP, FREAC3_01, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS, chr2q11, GOMF_TRANSPORTER_ACTIVITY, FOXO3_01, GOBP_MAGNESIUM_ION_HOMEOSTASIS, KASLER_HDAC7_TARGETS_1_UP, FEVR_CTNNB1_TARGETS_DN

GO Biological Process (3): monoatomic ion transport (GO:0006811), magnesium ion homeostasis (GO:0010960), transmembrane transport (GO:0055085)

GO Molecular Function (2): transmembrane transporter activity (GO:0022857), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
cellular process	1
transporter activity	1
transmembrane transport	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

954 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNNM3	PTP4A2	Q12974	962
CNNM3	H7C2H4	H7C2H4	853
CNNM3	P0DN79	P0DN79	834
CNNM3	SLC41A1	Q8IVJ1	672
CNNM3	NIPAL3	Q6P499	605
CNNM3	NIPAL2	Q9H841	595
CNNM3	NIPAL1	Q6NVV3	593
CNNM3	TRPM6	Q9BX84	593
CNNM3	NIPAL4	Q0D2K0	583
CNNM3	FAHD2B	Q6P2I3	571
CNNM3	NIPA2	Q8N8Q9	553
CNNM3	FAM178B	Q8IXR5	541
CNNM3	SLC41A3	Q96GZ6	515
CNNM3	TRPM7	Q96QT4	502
CNNM3	SLC41A2	Q96JW4	498

IntAct

317 interactions, top by confidence:

A	B	Type	Score
CNNM3	FHL3	psi-mi:“MI:0915”(physical association)	0.780
FHL3	CNNM3	psi-mi:“MI:0915”(physical association)	0.780
CNNM3	MDFI	psi-mi:“MI:0915”(physical association)	0.760
CNNM3	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.720
KRTAP10-8	CNNM3	psi-mi:“MI:0915”(physical association)	0.720
CNNM3	KRTAP10-9	psi-mi:“MI:0915”(physical association)	0.720
KRTAP5-9	CNNM3	psi-mi:“MI:0915”(physical association)	0.720
KRTAP10-9	CNNM3	psi-mi:“MI:0915”(physical association)	0.720
PTP4A2	PTP4A3	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
CCNDBP1	CNNM3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP2-3	CNNM3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-5	CNNM3	psi-mi:“MI:0915”(physical association)	0.560
CNNM3	CBY2	psi-mi:“MI:0915”(physical association)	0.560
PNMA1	CNNM3	psi-mi:“MI:0915”(physical association)	0.560
LZTS2	CNNM3	psi-mi:“MI:0915”(physical association)	0.560
CNNM3	CCNDBP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (278): CNNM3 (Two-hybrid), CNNM3 (Two-hybrid), CNNM3 (Two-hybrid), CNNM3 (Two-hybrid), USHBP1 (Two-hybrid), KRTAP3-2 (Two-hybrid), LZTS2 (Two-hybrid), KRTAP2-4 (Two-hybrid), SPERT (Two-hybrid), KRTAP10-9 (Two-hybrid), KRTAP10-5 (Two-hybrid), KRTAP10-8 (Two-hybrid), CNNM3 (Affinity Capture-MS), CNNM3 (Two-hybrid), KRTAP4-12 (Two-hybrid)

ESM2 similar proteins: A4FV98, A5PK51, A6NDG6, E1BE10, O00587, O35595, O95294, P60487, Q12788, Q17QS4, Q1JPJ0, Q2T9S4, Q2TBI8, Q32NY4, Q3T063, Q3ZBF9, Q501J2, Q5E9V4, Q5F4B1, Q5IS64, Q5SUV1, Q5T9C9, Q6AYG0, Q6AYR8, Q6XQN1, Q6XQN6, Q6ZMM2, Q80US4, Q8BNV1, Q8BZG5, Q8CC86, Q8IZ69, Q8N9H8, Q8NE01, Q8R2H9, Q8TCT1, Q8VCA8, Q8VD52, Q969S8, Q96AZ1

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.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	21	23.4×	6e-22

GO biological processes:

GO term	Partners	Fold	FDR
regulation of alternative mRNA splicing, via spliceosome	5	21.8×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	138
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1385 predictions. Top by Δscore:

Variant	Effect	Δscore
2:96817498:GCGAG:G	donor_gain	1.0000
2:96825053:CACA:C	acceptor_loss	1.0000
2:96825054:ACAG:A	acceptor_gain	1.0000
2:96825055:CA:C	acceptor_loss	1.0000
2:96825056:A:AG	acceptor_gain	1.0000
2:96825056:AG:A	acceptor_gain	1.0000
2:96825056:AGG:A	acceptor_gain	1.0000
2:96825057:G:A	acceptor_loss	1.0000
2:96825057:G:GA	acceptor_gain	1.0000
2:96825057:GG:G	acceptor_gain	1.0000
2:96825057:GGG:G	acceptor_gain	1.0000
2:96825057:GGGA:G	acceptor_gain	1.0000
2:96825057:GGGAA:G	acceptor_gain	1.0000
2:96825197:CTACC:C	donor_gain	1.0000
2:96825198:TACC:T	donor_gain	1.0000
2:96825199:ACC:A	donor_gain	1.0000
2:96825200:CC:C	donor_gain	1.0000
2:96825202:G:GG	donor_gain	1.0000
2:96826826:A:AG	acceptor_gain	1.0000
2:96826827:T:G	acceptor_gain	1.0000
2:96826830:TAG:T	acceptor_loss	1.0000
2:96826831:A:AG	acceptor_gain	1.0000
2:96826831:AG:A	acceptor_gain	1.0000
2:96826832:G:A	acceptor_loss	1.0000
2:96826832:G:GG	acceptor_gain	1.0000
2:96826832:GG:G	acceptor_gain	1.0000
2:96826832:GGA:G	acceptor_gain	1.0000
2:96826832:GGAGA:G	acceptor_gain	1.0000
2:96826931:G:GG	donor_gain	1.0000
2:96826979:CGAG:C	donor_loss	1.0000

AlphaMissense

4467 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:96817455:T:A	V393D	0.999
2:96817457:T:C	F394L	0.999
2:96817459:C:A	F394L	0.999
2:96817459:C:G	F394L	0.999
2:96817494:T:C	F406S	0.999
2:96825072:G:C	A414P	0.999
2:96825073:C:A	A414D	0.999
2:96825136:T:A	V435D	0.999
2:96817482:T:A	V402D	0.998
2:96825079:T:A	V416E	0.998
2:96825129:G:C	G433R	0.998
2:96827856:T:G	Y549D	0.998
2:96827890:T:C	L560P	0.998
2:96828106:T:A	V566D	0.998
2:96828138:T:C	F577L	0.998
2:96828140:T:A	F577L	0.998
2:96828140:T:G	F577L	0.998
2:96828153:T:C	F582L	0.998
2:96828155:C:A	F582L	0.998
2:96828155:C:G	F582L	0.998
2:96828166:G:A	G586E	0.998
2:96829011:T:G	Y646D	0.998
2:96817320:G:C	R348P	0.997
2:96817326:C:A	P350Q	0.997
2:96817457:T:A	F394I	0.997
2:96817485:T:C	L403P	0.997
2:96817493:T:C	F406L	0.997
2:96817495:C:A	F406L	0.997
2:96817495:C:G	F406L	0.997
2:96825070:T:C	L413P	0.997

dbSNP variants (sampled 300 via entrez): RS1000127740 (2:96815099 T>C,G), RS1000182020 (2:96815421 A>G), RS1000354178 (2:96821384 A>G), RS1000403109 (2:96827091 C>A,G,T), RS1000640626 (2:96822717 C>A,T), RS1000641398 (2:96829921 T>G), RS1000680235 (2:96818490 A>G,T), RS1001044115 (2:96835061 C>A), RS1001078352 (2:96817877 GA>G), RS1001140620 (2:96828367 C>T), RS1001240015 (2:96822106 G>A), RS1001296341 (2:96833230 G>A,C), RS1001412002 (2:96833413 G>A,C,T), RS1001469297 (2:96817721 G>C), RS1001471407 (2:96829679 A>G)

Disease associations

OMIM: gene MIM:607804 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000824_20	Erectile dysfunction and prostate cancer treatment	6.000000e-06
GCST008103_13	Bipolar disorder	4.000000e-09
GCST008362_203	Birth weight	3.000000e-09
GCST008363_28	Offspring birth weight	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases abundance, increases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
(+)-JQ1 compound	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	affects response to substance	1
Air Pollutants	increases abundance, affects expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Diazinon	increases methylation	1
Hydralazine	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Ozone	affects expression, increases abundance	1
Selenomethionine	affects expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1

Clinical trials (associated diseases)

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