TRPM3

Chr 9AD

transient receptor potential cation channel subfamily M member 3

Also known as: CTRCT50, GON-2, LTRPC3, MLSN2, NEDFSS

NCBI Gene: 80036ENSG00000083067UniProt: Q9HCF6

The product of this gene belongs to the family of transient receptor potential (TRP) channels. TRP channels are cation-selective channels important for cellular calcium signaling and homeostasis. The protein encoded by this gene mediates calcium entry, and this entry is potentiated by calcium store depletion. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Cataract 50 with or without glaucomaMIM #620253
AD
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizuresMIM #620224
AD
478
ClinVar variants
48
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— TRPM3
🧬
Gene-Disease Validity (ClinGen)
syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
48 Pathogenic / Likely Pathogenic· 354 VUS of 478 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
0.45LOEUF
pLI 0.000
Z-score 5.64
OE 0.33 (0.24–0.45)
Moderately constrained

More LoF-intolerant than ~75% 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.
3.18Z-score
OE missense 0.72 (0.67–0.76)
716 obs / 998.5 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.0.33 (0.24–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.67–0.76)
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.0.99
0≤1.21.6
LoF obs/exp: 27 / 82.2Missense obs/exp: 716 / 998.5Syn Z: 0.13

ClinVar Variant Classifications

478 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic15
VUS354
Likely Benign45
Benign26
Conflicting5
33
Pathogenic
15
Likely Pathogenic
354
VUS
45
Likely Benign
26
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
33
0
33
Likely Pathogenic
1
6
8
0
15
VUS
4
315
35
0
354
Likely Benign
0
15
7
23
45
Benign
0
5
7
14
26
Conflicting
—5
Total53419037478

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

View in ClinVar →

Protein Context — Lollipop Plot

TRPM3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TRPM3-related developmental disorder

definitive
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

?Cataract 50 with or without glaucoma

MIM #620253

Molecular basis of disorder known

Autosomal dominant

Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures

MIM #620224

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — TRPM3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone.
Löhn M et al.·J Transl Med
2024Review
Targeting TRP channels for pain relief: A review of current evidence from bench to bedside.
Koivisto AP et al.·Curr Opin Pharmacol
2024Review
Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders.
Burglen L et al.·Elife
2023
Phenotype Spectrum of TRPM3-Associated Disorders.
Jolitz L et al.·Ann Neurol
2025
Muscarinic Receptor Antagonism and TRPM3 Activation as Stimulators of Mitochondrial Function and Axonal Repair in Diabetic Sensorimotor Polyneuropathy.
Chauhan S et al.·Int J Mol Sci
2025Review
De novo TRPM3 missense variant associated with neurodevelopmental delay and manifestations of cerebral palsy.
Sundaramurthi JC et al.·Cold Spring Harb Mol Case Stud
2024
Identification and classification of a new TRPM3 variant (γ subtype).
Uchida K et al.·J Physiol Sci
2019
The role of TRP ion channels in migraine and headache.
Iannone LF et al.·Neurosci Lett
2022Review
Regulation of Pain and Itch by TRP Channels.
Moore C et al.·Neurosci Bull
2018Review
Primidone improves symptoms in TRPM3-linked developmental and epileptic encephalopathy with spike-and-wave activation in sleep.
Becker LL et al.·Epilepsia
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cryo-EM structure enabling virtual screening for the discovery of highly potent TRPM3 antagonists with analgesic efficacy.
Yang T et al.·Neuron
2026
ATP release mediated by TRPM3 enhances invasion in glioblastoma.
Bae KG et al.·Anim Cells Syst (Seoul)
2026🔓 Open Access
A duo of redox-sensitive pore-loop cysteines controls the activity of the neural ion channel TRPM3.
Held K et al.·Commun Chem
2026🔓 Open Access
Large-scale investigation confirms TRPM3 ion channel dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Sasso EM et al.·Front Med (Lausanne)
2025🔓 Open Access
Modulation of Cognitive Function by TRPM3 Channels in the Dentate Gyrus of a Menopausal Rat Model: Effects of Naringenin Treatment and Ciliary Neurotrophic Factor.
Shirasath KR et al.·J Neuroimmune Pharmacol
2026Functional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Vitiligo

TRPM2 Gene Polymorphism, NLRP3 Inflammasome Expression in Vitiligo Patients

ACTIVE NOT RECRUITING
NCT07232238Aswan UniversityStarted 2025-10-20

External Resources

Links to major genomics databases and tools