TRPM4

protein-coding

transient receptor potential cation channel subfamily M member 4, the group of Transient receptor potential cation channels

Gene summary

The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

MANE transcript

NM_017636.4

Inheritance

ClinVar variants

P:8U:1219B:600

Top phenotype

Progressive familial heart block, type IB

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr19:49,157,741-49,211,836

External References & Databases

Ensembl (ENSG00000130529)

Transcript & Mutation Effects

hg38 • Region Span ~54.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

progressive familial heart block type IBMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011474

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

erythrokeratodermia variabilisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017851

Submitter: Orphanet

progressive familial heart block type IBMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011474

Submitter: PanelApp Australia

erythrokeratodermia variabilis et progressiva 6MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032801

Submitter: PanelApp Australia

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: ClinGen

TRPM4 encodes a homotetrameric calcium-activated nonselective cation channel. The TRPM4 channel is only permeable to monovalent ions and has been proposed to facilitate the influx of Na+ during depolarisation and the efflux of K+ during repolarisation (PMIDs: 24721656, 25441424). The relationship between TRPM4 and autosomal dominant Brugada syndrome was initially suggested by Liu et al. in 2013 following the identification of 11 unique variants in a cohort of patients with SCN5A-negative Brugada syndrome (PMID:23382873). Two further publications have reported TRPM4 variants in two patients with Brugada syndrome, including a carrier of compound heterozygous null TRPM4 variants (PMIDs: 28494446, 30142439). This collective clinical genetic evidence is insufficient for establishing a causal relationship between TRPM4 and autosomal dominant Brugada syndrome: 1. While some rare variants have been reported, many of the variants have population frequencies that are too high for a severe autosomal dominant condition such as Brugada syndrome. 2. The suggested mechanism of disease appears to be haploinsufficiency, yet TRPM4 is tolerant to nonsense variation (pLi=0, LOEUF=1.084, gnomAD v 4.1). Consistent with this tolerance to nonsense variation, the relatively common p.Lys914Ter variant (AF= 1.02x10-3) reported by Liu et al. results in a greater decrease in current density in transfected cell models than the rare p.Pro779Arg variant. 3. Burden testing has failed to identify any statistically significant enrichment of TRPM4 variants in patients with Brugada syndrome relative to controls (PMID: 25650408). The relationship between TRPM4 and autosomal dominant Brugada syndrome was originally evaluated by the ClinGen Brugada Syndrome Gene Curation Expert Panel in 2017 and was classified as disputed. This gene-disease pair was re-evaluated by the Hereditary Cardiovascular Disorders GCEP on 11 November, 2025. Following re-evaluation and the consideration of new evidence, the gene-disease classification was changed to refuted. This classification was approved by the ClinGen Hereditary Cardiovascular Disorders GCEP on 11 November, 2025 (in accordance with SOP Version 11).

progressive familial heart block type IBSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011474

Submitter: Labcorp Genetics (formerly Invitae)

progressive familial heart blockSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019490

Submitter: Orphanet

erythrokeratodermia variabilis et progressiva 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032801

Submitter: Labcorp Genetics (formerly Invitae)

progressive familial heart block type IBMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011474

Submitter: Genomics England PanelApp

erythrokeratodermia variabilis et progressiva 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032801

Submitter: Ambry Genetics

Brugada syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Genomics England PanelApp

erythrokeratodermia variabilis et progressiva 6MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032801

Submitter: G2P

Clinical Genomic Database (CGD)

Progressive familial heart block, type IBAD

Manifestation: Cardiovascular; Dermatologic

Intervention: Cardiovascular

Rationale: Preventive measures (eg, pacemakers and other medical measures) have been shown to be effective to control sequelae, which can include sudden death

Refs: 897853; 619595; 4003252; 3750143; 3347879; 9023172; 19726882; 20562447; 21887725; 30528822

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRPM4 variants in ClinVar

23 Conditions Cataloged

Progressive familial heart block type IBTotal: 1636

Cardiovascular phenotypeTotal: 1140

not providedTotal: 391

not specifiedTotal: 192

Erythrokeratodermia variabilis et progressiva 6Total: 92

TRPM4-related disorderTotal: 46

CardiomyopathyTotal: 9

Long QT syndromeTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017636.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	22 clinvar	482 clinvar	6 clinvar	511
missense	2 clinvar	4 clinvar	1039 clinvar	100 clinvar	5 clinvar	1150
nonsense		1 clinvar	27 clinvar	4 clinvar	1 clinvar	33
start loss			4 clinvar			4
frameshift			70 clinvar	1 clinvar		71
splice donor/acceptor (+/-2bp)			57 clinvar	1 clinvar		58
Total	2	6	1219	588	12	1827

Highest pathogenic variant AF is 0.0000074355526

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017636.4	RefSeq	NP_060106.2	25	MANE Select
ENST00000252826.10	Ensembl	ENSP00000252826.4	25	MANE Select
NM_001195227.2	RefSeq	NP_001182156.1	24	Standard
NM_001321281.2	RefSeq	NP_001308210.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Insulin secretion - Homo sapiens (human)
Stimuli-sensing channels
Ion channel transport
Transport of small molecules
TRP channels

Biological Process

adaptive immune response
dendritic cell chemotaxis
regulation of T cell cytokine production
positive regulation of cytosolic calcium ion concentration
positive regulation of cell population proliferation

Molecular Function

calcium activated cation channel activity
calcium channel activity
sodium channel activity
calcium ion binding
calmodulin binding

Cellular Component

nucleoplasm
endoplasmic reticulum
Golgi apparatus
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252826
Coding exons: 25
Length: 54096
Individuals with no LoFs: 124793
Homozygous LoFs: 1
Heterozygous LoFs: 954
Defined: 125748
p: 0.00380

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.966	726	803	0.904	0.0000578	7740
Missense (PolyPhen)		205	239.87	0.85464		2509
Synonymous	1.08	316	341	0.926	0.0000245	2580
Loss of Function	0.900	54	61.6	0.876	0.00000324	619

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0010	0.00092	rare
Latino/Admixed American	0.0017	0.0016	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0060	0.0060	notable
Finnish	0.0078	0.0074	notable
European (Non-Finnish)	0.0050	0.0048	notable
South Asian	0.0015	0.0015	notable
Other	0.0043	0.0041	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization (PubMed:12015988, PubMed:29211723). While it is activated by increase in intracellular Ca(2+), it is impermeable to it (PubMed:12015988). Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway. {ECO:0000269|PubMed:11535825, ECO:0000269|PubMed:12015988, ECO:0000269|PubMed:12799367, ECO:0000269|PubMed:14758478, ECO:0000269|PubMed:15121803, ECO:0000269|PubMed:15331675, ECO:0000269|PubMed:15472118, ECO:0000269|PubMed:15550671, ECO:0000269|PubMed:15590641, ECO:0000269|PubMed:15845551, ECO:0000269|PubMed:16186107, ECO:0000269|PubMed:16407466, ECO:0000269|PubMed:16424899, ECO:0000269|PubMed:16806463, ECO:0000269|PubMed:20625999, ECO:0000269|PubMed:20656926, ECO:0000269|PubMed:29211723}.;
Disease: DISEASE: Progressive familial heart block 1B (PFHB1B) [MIM:604559]: A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His- Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death. {ECO:0000269|PubMed:19726882, ECO:0000269|PubMed:20562447, ECO:0000269|PubMed:21887725}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.104

Intolerance Scores

LoFtool: 0.752
RVIS EVS: -1.14
RVIS percentile EVS: 6.39

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0981

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium