CNNM3

Chr 2

cyclin and CBS domain divalent metal cation transport mediator 3

Also known as: ACDP3, SLC70A3

NCBI Gene: 26505ENSG00000168763UniProt: Q8NE01

The CNNM3 protein is a transmembrane metal transporter involved in magnesium ion homeostasis. Mutations cause autosomal recessive hypomagnesemia with seizures and intellectual disability, typically presenting in infancy or early childhood. The gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
4
Pubs (1 yr)
32
P/LP submissions
0%
P/LP missense
0.97
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— CNNM3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
32 unique Pathogenic / Likely Pathogenic· 167 VUS of 216 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.97LOEUF
pLI 0.000
Z-score 1.66
OE 0.62 (0.41–0.97)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.76Z-score
OE missense 0.88 (0.79–0.97)
256 obs / 292.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.62 (0.41–0.97)
0≤0.351.4
Missense OE0.88 (0.79–0.97)
0≤0.61.4
Synonymous OE1.05
0≤1.21.6
LoF obs/exp: 14 / 22.5Missense obs/exp: 256 / 292.4Syn Z: -0.47
DN
0.6646th %ile
GOF
0.79top 10%
LOF
0.3453th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

216 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic10
VUS167
Likely Benign5
22
Pathogenic
10
Likely Pathogenic
167
VUS
5
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
22
0
22
Likely Pathogenic
0
0
10
0
10
VUS
0
137
30
0
167
Likely Benign
0
3
2
0
5
Benign
0
0
0
0
0
Total0140640204

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

View in ClinVar →

Protein Context — Lollipop Plot

CNNM3 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 2 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients