TRPM6

Chr 9AR

transient receptor potential cation channel subfamily M member 6

Also known as: CHAK2, HMGX, HOMG, HOMG1, HSH

NCBI Gene: 140803ENSG00000119121UniProt: Q9BX84OMIM: 607009

This protein is a bifunctional magnesium channel with an intrinsic kinase domain that is crucial for magnesium homeostasis and active magnesium absorption in the gut and kidney. Autosomal recessive mutations cause hypomagnesemia with secondary hypocalcemia (hypomagnesemia 1, intestinal), resulting from impaired epithelial magnesium transport. The pathogenic mechanism involves loss of function of either the ion channel activity or the kinase domain function.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
MultiplemechanismARLOEUF 0.451 OMIM phenotype
Clinical Summary— TRPM6
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
12 unique Pathogenic / Likely Pathogenic· 100 VUS of 200 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — TRPM6
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.45LOEUF
pLI 0.000
Z-score 6.37
OE 0.34 (0.27–0.45)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.61Z-score
OE missense 0.86 (0.81–0.91)
885 obs / 1030.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.34 (0.27–0.45)
0≤0.351.4
Missense OE0.86 (0.81–0.91)
0≤0.61.4
Synonymous OE1.09
0≤1.21.6
LoF obs/exp: 38 / 110.2Missense obs/exp: 885 / 1030.5Syn Z: -1.40
DN
0.7326th %ile
GOF
0.7127th %ile
LOF
0.2969th %ile

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

DNprediction above median
GOFprediction above median
LOF92% of P/LP variants are LoF · LOEUF 0.45

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic6
VUS100
Likely Benign76
6
Pathogenic
6
Likely Pathogenic
100
VUS
76
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
1
0
6
Likely Pathogenic
6
0
0
0
6
VUS
0
96
2
2
100
Likely Benign
0
3
32
41
76
Benign
0
0
0
0
0
Total11993543188

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

View in ClinVar →

Protein Context — Lollipop Plot

TRPM6 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

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 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Chronic magnesium supplementation in a patient with relapsing severe hypomagnesaemia due to a novel TRPM6 variant diagnosed in adulthood.
Bogaert EG et al.·BMJ Case Rep
2026Open Access
A Comparison of Marine and Non-Marine Magnesium Sources for Bioavailability and Modulation of TRPM6/TRPM7 Gene Expression in a Caco-2 Epithelial Cell Model.
Demehin OA et al.·Nutrients
2026Open AccessFunctional
TRPM6 acts as a prognostic biomarker and mediates Mg2+ dependent tumor suppression in colon adenocarcinoma.
Cao L et al.·Front Immunol
2025Open Access
[A case report of primary hypomagnesemia with secondary hypocalcemia caused by TRPM6 gene variants].
Zhou MY et al.·Zhongguo Dang Dai Er Ke Za Zhi
2026Case report
Familial hypomagnesaemia with secondary hypocalcaemia: novel TRPM6 variant.
Alvelos R et al.·BMJ Case Rep
2025
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