CNNM2

Chr 10ADAR

cyclin and CBS domain divalent metal cation transport mediator 2

Also known as: ACDP2, HOMG6, HOMGSMR, SLC70A2

NCBI Gene: 54805ENSG00000148842UniProt: Q9H8M5

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. [provided by RefSeq, Dec 2011]

Primary Disease Associations & Inheritance

Hypomagnesemia 6, renalMIM #613882
AD
Hypomagnesemia, seizures, and impaired intellectual development 1MIM #616418
ADAR
560
ClinVar variants
39
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— CNNM2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
39 Pathogenic / Likely Pathogenic· 197 VUS of 560 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.27LOEUF
pLI 0.995
Z-score 4.48
OE 0.10 (0.05–0.27)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
4.41Z-score
OE missense 0.44 (0.40–0.49)
219 obs / 495.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.10 (0.05–0.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.44 (0.40–0.49)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10
0≤1.21.6
LoF obs/exp: 3 / 29.0Missense obs/exp: 219 / 495.2Syn Z: -1.19

ClinVar Variant Classifications

560 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic10
VUS197
Likely Benign93
Benign24
Conflicting6
29
Pathogenic
10
Likely Pathogenic
197
VUS
93
Likely Benign
24
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
7
18
0
29
Likely Pathogenic
2
6
2
0
10
VUS
4
163
26
4
197
Likely Benign
0
5
20
68
93
Benign
0
1
17
6
24
Conflicting
—6
Total101828378359

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CNNM2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CNNM2-related neurodevelopmental disorder with hypomagnesemia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

CNNM2-related neurodevelopmental disorder with hypomagnesemia

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CYCLIN M2; CNNM2
MIM #607803 · *

Hypomagnesemia 6, renal

MIM #613882

Molecular basis of disorder known

Autosomal dominant

Hypomagnesemia, seizures, and impaired intellectual development 1

MIM #616418

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Magnesium in man: implications for health and disease.
de Baaij JH et al.·Physiol Rev
2015Review
Gene-level analysis reveals the genetic aetiology and therapeutic targets of schizophrenia.
Dang X et al.·Nat Hum Behav
2025Meta-analysis
Novel CNNM2 variant causing hypomagnesemia and early-onset calcium pyrophosphate deposition disease: A case report.
Robert C et al.·Joint Bone Spine
2026Case report
[Analysis of CNNM2 gene variant in a child with Hypomagnesemia, seizures, and mental retardation syndrome].
Wang L et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2023Case report
Association and shared biological bases between birth weight and cortical structure.
Zhang L et al.·Transl Psychiatry
2025
Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants.
Bosman W et al.·Sci Rep
2024
Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk: Mendelian Randomization and Colocalization Study.
Bakker MK et al.·Stroke
2023
CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia.
Arjona FJ et al.·PLoS Genet
2014Cohort
Rare hypomagnesemia, seizures, and mental retardation in a 4-month-old patient caused by novel CNNM2 mutation Tyr189Cys: Genetic analysis and review.
Xu X et al.·Mol Genet Genomic Med
2022Case report
Novel variant in the CNNM2 gene associated with dominant hypomagnesemia.
García-Castaño A et al.·PLoS One
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools