CNNM3

Chr 2

cyclin and CBS domain divalent metal cation transport mediator 3

Also known as: ACDP3, SLC70A3

NCBI Gene: 26505 ENSG00000168763 UniProt: Q8NE01 OMIM: 607804

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.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable transmembrane transporter activity. Predicted to be involved in magnesium ion homeostasis. Located in membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.97

Clinical Summary— CNNM3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 137 VUS of 153 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 OE?0.62 (0.41–0.97)

0≤0.351.4

Missense OE?0.88 (0.79–0.97)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 14 / 22.5Missense obs/exp: 256 / 292.4Syn Z: -0.47

This gene — mechanism propensity

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

153 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS137

Likely Benign3

Pathogenic

137

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	1	1
Likely Pathogenic	0	0	0
VUS	137	0	137
Likely Benign	3	0	3
Benign	0	0	0
Total	140	1	141

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 63) ClinVar copy-number / structural variants overlap CNNM3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →