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 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 152 total
• GTEx eGene: eQTL in 28 tissues, sQTL in 5 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.23 (unconstrained)
• MANE Select transcript: NM_017623
• Notable: 152 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 24 — 13 nonsense_mediated_decay, 8 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000305510

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

ENST00000305510, ENST00000377060, ENST00000465224, ENST00000480035, ENST00000494595, ENST00000867797, ENST00000947262, ENST00000947263, ENST00000947264, ENST00000947265, ENST00000994569, ENST00000994570, ENST00000994571, ENST00001042029, ENST00001042030, ENST00001042031, ENST00001042032, ENST00001042033, ENST00001042034, ENST00001084230, ENST00001084231, ENST00001084232, ENST00001128237, ENST00001142640

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
ENSE00004801317	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.

Highest expression (Bgee): gastrocnemius, muscle of leg, cerebellar hemisphere, hemisphere of cerebellum, cerebellar cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CNNM3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 28 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 33 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Not Sun Exposed Suprapubic	eqtl	1.3e-17	+0.54	2:96816264:G:A
Skin Sun Exposed Lower leg	eqtl	6.2e-16	+0.46	2:96862362:A:G
Muscle Skeletal	eqtl	1.0e-13	+0.73	2:96838010:C:T
Nerve Tibial	eqtl	1.4e-09	+0.39	2:96861226:C:T
Adipose Subcutaneous	eqtl	7.6e-09	+0.42	2:96816264:G:A
Thyroid	eqtl	3.1e-08	+0.42	2:96816264:G:A
Pancreas	eqtl	8.3e-08	-0.32	2:96802539:G:C
Esophagus Muscularis	eqtl	1.3e-07	+0.23	2:96792112:G:A
Esophagus Mucosa	eqtl	1.6e-07	+0.43	2:96816264:G:A
Artery Tibial	eqtl	3.1e-07	+0.36	2:96617939:T:C
Lung	eqtl	7.8e-07	+0.38	2:96816264:G:A
Cells Cultured fibroblasts	eqtl	1.1e-06	+0.40	2:96816264:G:A
Breast Mammary Tissue	eqtl	5.0e-05	+0.45	2:95914657:T:C
Colon Sigmoid	eqtl	5.4e-05	+0.36	2:96862362:A:G
Kidney Cortex	sqtl	2.9e-04	-1.89	2:96797333:C:T
Adipose Visceral Omentum	eqtl	3.0e-04	+0.27	2:96900314:C:T
Heart Atrial Appendage	eqtl	4.1e-04	+0.42	2:96816264:G:A
Esophagus Gastroesophageal Junction	eqtl	1.2e-03	+0.46	2:96862362:A:G
Colon Transverse	eqtl	1.4e-03	+0.39	2:96816264:G:A
Prostate	eqtl	3.1e-03	+0.59	2:96861226:C:T

FANTOM5 promoters

2 alternative TSS:

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

Top tissues by expression

showing 100 of 285 tissues 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
small intestine Peyer’s patch	UBERON:0003454	88.28	gold quality
gall bladder	UBERON:0002110	88.17	gold quality
adenohypophysis	UBERON:0002196	88.01	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.90	gold quality
granulocyte	CL:0000094	87.89	gold quality
right lobe of thyroid gland	UBERON:0001119	87.88	gold quality
left uterine tube	UBERON:0001303	87.88	gold quality
lower esophagus	UBERON:0013473	87.88	gold quality
renal medulla	UBERON:0000362	87.77	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.72	gold quality
stomach	UBERON:0000945	87.64	gold quality
minor salivary gland	UBERON:0001830	87.64	gold quality
apex of heart	UBERON:0002098	87.60	gold quality
small intestine	UBERON:0002108	87.59	gold quality
spleen	UBERON:0002106	87.54	gold quality
right testis	UBERON:0004534	87.51	gold quality
inferior vagus X ganglion	UBERON:0005363	87.23	gold quality
left testis	UBERON:0004533	87.22	gold quality
lymph node	UBERON:0000029	87.13	gold quality
ectocervix	UBERON:0012249	87.12	gold quality
ovary	UBERON:0000992	87.06	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.99	gold quality
left lobe of thyroid gland	UBERON:0001120	86.78	gold quality
right frontal lobe	UBERON:0002810	86.46	gold quality
thyroid gland	UBERON:0002046	86.45	gold quality
transverse colon	UBERON:0001157	86.41	gold quality
liver	UBERON:0002107	86.41	gold quality
trachea	UBERON:0003126	86.36	gold quality
right coronary artery	UBERON:0001625	86.35	gold quality
ventral tegmental area	UBERON:0002691	86.30	gold quality
spinal cord	UBERON:0002240	86.28	gold quality
skeletal muscle organ	UBERON:0014892	86.27	gold quality
muscle organ	UBERON:0001630	86.26	gold quality
right adrenal gland	UBERON:0001233	85.92	gold quality
popliteal artery	UBERON:0002250	85.88	gold quality
tibial artery	UBERON:0007610	85.87	gold quality
right lung	UBERON:0002167	85.81	gold quality
left adrenal gland cortex	UBERON:0035825	85.75	gold quality
superior surface of tongue	UBERON:0007371	85.70	gold quality
testis	UBERON:0000473	85.60	gold quality
left adrenal gland	UBERON:0001234	85.60	gold quality
adrenal cortex	UBERON:0001235	85.60	gold quality
right adrenal gland cortex	UBERON:0035827	85.59	gold quality
metanephros cortex	UBERON:0010533	85.57	gold quality
saliva-secreting gland	UBERON:0001044	85.55	gold quality
caput epididymis	UBERON:0004358	85.49	gold quality
right atrium auricular region	UBERON:0006631	85.46	gold quality
coronary artery	UBERON:0001621	85.32	gold quality
mouth mucosa	UBERON:0003729	85.30	gold quality
colon	UBERON:0001155	85.24	gold quality
skin of abdomen	UBERON:0001416	85.20	gold quality
nucleus accumbens	UBERON:0001882	85.18	gold quality
skin of leg	UBERON:0001511	85.14	gold quality
intestine	UBERON:0000160	85.13	gold quality
adrenal gland	UBERON:0002369	85.10	gold quality
rectum	UBERON:0001052	84.99	gold quality
left coronary artery	UBERON:0001626	84.98	gold quality
aorta	UBERON:0000947	84.95	gold quality
corpus callosum	UBERON:0002336	84.92	gold quality
prefrontal cortex	UBERON:0000451	84.84	gold quality
duodenum	UBERON:0002114	84.82	gold quality
embryo	UBERON:0000922	84.81	gold quality
upper lobe of left lung	UBERON:0008952	84.80	gold quality
vagina	UBERON:0000996	84.73	gold quality
trigeminal ganglion	UBERON:0001675	84.69	gold quality
dorsal root ganglion	UBERON:0000044	84.67	gold quality
cerebellar vermis	UBERON:0004720	84.65	gold quality
upper lobe of lung	UBERON:0008948	84.58	gold quality
thymus	UBERON:0002370	84.53	gold quality
large intestine	UBERON:0000059	84.49	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	42.2	high
Pancreas	tissue	25.1	high
Cerebellum	tissue	22.6	high
Hippocampal formation	tissue	21.8
Cerebral cortex	tissue	20.2	high
Somatosensory cortex	tissue	20.2
Parathyroid gland	tissue	20.1
Thalamus	tissue	19.8
Superior colliculi	tissue	19.7
Midbrain	tissue	19.2
Hypothalamus	tissue	18.8
Pons	tissue	18.7
Liver	tissue	18.7	high
Choroid plexus	tissue	18.5
Spinal cord	tissue	18.4
Septum	tissue	18.3
Substantia nigra	tissue	18.1
Nucleus accumbens	tissue	18.0
Medulla oblongata	tissue	17.8
Ventral forebrain	tissue	17.8
Basal ganglia	tissue	17.3	medium
Periaqueductal gray	tissue	17.3
Corpus callosum	tissue	17.1
Motor cortex	tissue	16.9
Occipital cortex	tissue	16.8
Retrosplenial and cingulate cortex	tissue	16.5
Olfactory bulb	tissue	16.5
Prefrontal cortex	tissue	16.3
Entorhinal cortex	tissue	16.3
Amygdala	tissue	16.2
Duodenum	tissue	16.2	high
Temporal cortex	tissue	16.2
Insular cortex	tissue	16.2
Putamen	tissue	16.1
Hippocampus	tissue	15.6	medium
Retrosplenial cortex	tissue	15.3
Locus coeruleus	tissue	14.8
Small intestine	tissue	13.4	high
Postcentral gyrus	tissue	12.4
Retina	tissue	12.1
Stomach 1	tissue	11.7	medium
Salivary gland	tissue	11.7	medium
Thymus	tissue	10.7
Pituitary gland	tissue	10.5
Fallopian tube	tissue	10.2	high
Placenta	tissue	9.6	high
Spleen	tissue	8.9	medium
Caudate putamen	tissue	8.9
Gallbladder	tissue	8.8	high
Lung	tissue	8.6	medium
Lymph node	tissue	8.5	medium
Seminal vesicle	tissue	8.5	medium
Prostate	tissue	8.4	medium
Adrenal gland	tissue	8.4	high
Rectum	tissue	8.3	high
Colon	tissue	8.3	high
Ovary	tissue	8.2	high
Frontal cortex	tissue	8.2
Skin 1	tissue	8.0	high
Vagina	tissue	8.0	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Flocculonodular lobe (32.8), Cerebellar cortex (31.4), Vermis (30.2), Parieto-temporal junction (white matter) (26.7), Temporal white matter (26.5).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CNNM3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 150 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 2.35e-16, LOEUF 1.23, missense Z -1.72 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000305510 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:96,816,278–96,817,127	466 / 403.1	1.16	no
2:96,817,128–96,832,613	491 / 570.6	0.86	no

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)

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
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2	P0A2L3	100.0%	Diamond
Salmonella enterica subsp. enterica serovar Typhi	P0A2L4	100.0%	Diamond
Escherichia coli K-12	P0AE78	100.0%	Diamond
Escherichia coli CFT073	P0AE79	100.0%	Diamond
Escherichia coli O157:H7	P0AE80	100.0%	Diamond
Shigella flexneri	P0AE81	100.0%	Diamond
Rickettsia prowazekii str. Madrid E	O05961	93.8%	Diamond
Rickettsia typhi str. Wilmington	Q68W10	93.7%	Diamond
Haemophilus influenzae Rd KW20	Q57368	81.3%	Diamond
Pasteurella multocida subsp. multocida str. Pm70	Q9CM13	81.3%	Diamond
Arabidopsis thaliana	Q84R21	79.7%	Diamond
Vibrio cholerae O1 biovar El Tor str. N16961	Q9KTE3	66.8%	Diamond
Xenopus tropicalis	A0JPA0	66.1%	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
CNNM3-DT	ncRNA	100506036
CNNM4	protein-coding	26504
LMAN2L	protein-coding	81562
FER1L5	protein-coding	90342
MIR3127	ncRNA	100422928
ANKRD23	protein-coding	200539
ANKRD39	protein-coding	51239
SEMA4C	protein-coding	54910
FAM178B	protein-coding	51252

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 (59 total): helix 16, strand 16, 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 by resolution:

PDB	Title	Method	Resolution (Å)
6DFD	Crystal structure of CNNM3 cyclic nucleotide-binding homology domain	X-RAY DIFFRACTION	1.9
6WUR	Crystal structure of PRL-2 phosphatase C101D mutant in complex with the Bateman domain of …	X-RAY DIFFRACTION	2.88
5K23	Crystal structure of the complex between human phosphatase PRL-2 in the oxidized state …	X-RAY DIFFRACTION	2.96
5K22	Crystal structure of the complex between human PRL-2 phosphatase in reduced state and …	X-RAY DIFFRACTION	3
5K25	Crystal structure of human phosphatase PRL-2 in complex with the ADP-bound Bateman domain …	X-RAY DIFFRACTION	3.05
5TSR	Crystal structure of PRL-3 phosphatase in complex with the Bateman domain of CNNM3 …	X-RAY DIFFRACTION	3.19
6MN6	Crystal structure of the cytosolic domain of human CNNM3	X-RAY DIFFRACTION	3.36

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH supported · IF approved

Functional residue map

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

Post-translational modifications (2)

Type	Positions
Phosphoserine	661, 700

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	73

Function

Pathways and Gene Ontology

Reactome pathways

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

MSigDB gene sets: 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

10 GO namespaces:

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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 7 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
membrane	CC	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 574 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNNM3	SLC41A1	Q8IVJ1	608
CNNM3	PTP4A2	Q12974	575
CNNM3	NIPAL1	Q6NVV3	574
CNNM3	NIPAL3	Q6P499	571
CNNM3	NIPAL2	Q9H841	571
CNNM3	TRPM6	Q9BX84	547
CNNM3	ARL15	Q9NXU5	547
CNNM3	NIPAL4	Q0D2K0	544
CNNM3	NIPA2	Q8N8Q9	505
CNNM3	FAHD2B	Q6P2I3	498
CNNM3	TRPM7	Q96QT4	495
CNNM3	FAM178B	Q8IXR5	492
CNNM3	SLC41A2	Q96JW4	477
CNNM3	COX11	Q9Y6N1	460
CNNM3	SLC41A3	Q96GZ6	429

IntAct

Human interaction partners of CNNM3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 69 partners by confidence:

Partner	Interaction type	MIscore	Records
FHL3	physical association	0.780	9
MDFI	physical association	0.760	6
KRTAP10-8	physical association	0.720	6
KRTAP10-9	physical association	0.720	6
KRTAP5-9	physical association	0.720	6
CBY2	physical association	0.560	6
HOXA1	physical association	0.560	5
KRTAP10-7	physical association	0.560	5
KRTAP17-1	physical association	0.560	5
VWC2	physical association	0.560	5
HNRNPK	physical association	0.560	4
RBPMS	physical association	0.560	4
ACTN2	physical association	0.560	3
AGR2	physical association	0.560	3
AGR3	physical association	0.560	3
AKAP8L	physical association	0.560	3
CALCOCO2	physical association	0.560	3
CARD10	physical association	0.560	3
CCNDBP1	physical association	0.560	3
COG6	physical association	0.560	3
CYSRT1	physical association	0.560	3
EFEMP2	physical association	0.560	3
EXOSC8	physical association	0.560	3
FHL5	physical association	0.560	3
GOLGA6L9	physical association	0.560	3
HSF2BP	physical association	0.560	3
KHDRBS2	physical association	0.560	3
KHDRBS3	physical association	0.560	3
KPRP	physical association	0.560	3
KRT31	physical association	0.560	3

BioGRID (279 interactions; top human partners by supporting records): PTP4A2 (Affinity Capture-MS; 9 records), PTP4A1 (Affinity Capture-MS; 7 records), KRAS (Proximity Label-MS; 4 records), FHL3 (Two-hybrid; 3 records), HRAS (Proximity Label-MS; 3 records), LAMP1 (Proximity Label-MS; 3 records), MDFI (Two-hybrid; 3 records), PTP4A3 (Affinity Capture-MS; 3 records), ARL15 (Affinity Capture-MS; 2 records), CANX (Affinity Capture-MS; 2 records), CLEC4E (Affinity Capture-MS; 2 records), DPP4 (Affinity Capture-MS; 2 records), FBXO6 (Affinity Capture-MS; 2 records), HNRNPK (Two-hybrid; 2 records), ILK (Affinity Capture-MS; 2 records)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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	27.9×	5e-24

GO biological processes:

GO term	Partners	Fold	FDR
regulation of alternative mRNA splicing, via spliceosome	5	26.6×	3e-04

Disease & clinical

Genetic variants

Variant evidence for CNNM3: 152 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	137
Likely benign	3
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 682):

Position(s)	Effect	Δscore	Sites
2:96825056–96825057	acceptor_loss	1.0000	4
2:96826827	acceptor_gain	1.0000
2:96826831–96826832	acceptor_loss	1.0000	2
2:96826983–96826984	donor_loss	1.0000	5
2:96827721	acceptor_gain	1.0000
2:96827724	acceptor_gain	1.0000
2:96827730	acceptor_loss	1.0000
2:96827901–96827902	donor_loss	1.0000	5
2:96817503–96817504	donor_loss	0.9900	5
2:96825056–96825057	acceptor_loss	0.9900	2

AlphaMissense

1,229 missense substitutions predicted likely pathogenic (of 4,467 scored), across 349 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
D439	8	0.985	0.993
D426	8	0.984	0.996
D396	8	0.981	0.996
F406	8	0.981	0.999
F511	8	0.974	0.995
F582	8	0.974	0.998
F394	8	0.972	0.999
H412	8	0.967	0.991
D367	8	0.960	0.989
F577	8	0.954	0.998
F558	8	0.946	0.993
D627	8	0.903	0.967
D451	8	0.875	0.935
N420	8	0.862	0.978
D400	8	0.855	0.923
D375	8	0.802	0.936
F370	8	0.769	0.931
F503	7	0.982	0.997
F385	7	0.964	0.994
E438	7	0.960	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	5.18e-09
Kidney Renal Clear Cell Carcinoma (validation)	favorable	3.55e-07

Disease associations

OMIM: gene MIM:607804 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST008362_161	Birth weight	3e-9
GCST008103_173	Bipolar disorder	4e-9
GCST008363_3	Offspring birth weight	5e-6
GCST000824_20	Erectile dysfunction and prostate cancer treatment	6e-6

EFO canonical traits (from GWAS)

2 canonical traits:

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 (CPIC guideline: no)

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	affects expression, increases abundance	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)

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