Mutations
TREM2
TREM2 encodes Triggering Receptor Expressed on Myeloid Cells 2, a transmembrane receptor that modulates microglial activity and survival. TREM2 variants cause Nasu-Hakola disease (NHD), a rare autosomal recessive early-onset dementia, and may modify the risk of developing Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).

Search Results
TREM2 (68)
Mutation | Clinical Phenotype |
Pathogenicity | Neuropathology | Biological Effect | Genomic Position | Genomic Region | Mutation Type Codon Change |
Research Models |
Primary Papers |
---|---|---|---|---|---|---|---|---|---|
G219C |
AD : Unclear Pathogenicity | Unknown. | Predicted by SIFT to be damaging but by Polyphen2 to be benign. | rs768583708 |
Coding Exon 4 of transcript variant 2 |
Point, Missense GGT to TGT |
0 | Ghani et al., 2016 | |
L205P |
AD : Unclear Pathogenicity | Unknown. | Predicted by SIFT to be damaging, but by Polyphen2 to be benign. | Coding Exon 4 of transcript variant 2 |
Point, Missense CTG to CCG |
0 | Ghani et al., 2016 | ||
E202D |
AD : Unclear Pathogenicity | Unknown. | Unknown. | rs530314472 |
Coding Exon 4 of transcript variant 2 |
Point, Missense GAG to GAT |
0 | Jin et al., 2014; Jin et al., 2015 |
|
W200C |
AD : Unclear Pathogenicity | Unknown. | Predicted to be probably damaging by Polyphen2. | Coding Exon 4 of transcript variant 2 |
Point, Missense TGG to TGC |
0 | Jiang et al., 2016 | ||
W191X |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Unknown. | rs2234258 |
Coding Exon 4 of transcript variant 2 |
Point, Nonsense TGG to TAG |
0 | Jin et al., 2015 |
rs2234258 |
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown. | Unknown. | rs2234258 |
Non-Coding 3' UTR |
Point |
0 | Cuyvers et al., 2014 | |
S183C |
AD : Unclear Pathogenicity | Unknown. | Predicted to be tolerated by SIFT but possibly damaging by PolyPhen-2; classified as a polymorphism by Mutation Taster. | rs200820365 |
Coding Exon 4 of transcript variant 2 |
Point, Missense AGC to TGC |
0 | Jiang et al., 2016; Zhang et al., 2020 |
|
T223I |
AD : Benign, FTD : Unclear Pathogenicity | Unknown. | Predicted by Polyphen2 to be benign, by SIFT to be tolerated and by SNPs&Go to be neutral; normal protein maturation in HEK293 cells. | rs138355759 |
Coding Exon 4 |
Point, Missense ACT to ATT |
0 | Sims et al., 2017 | |
H215Q |
AD : Unclear Pathogenicity | Unknown. | Unknown. | Coding Exon 4 |
Point, Missense CAT to CAG |
0 | Jin et al., 2014 | ||
L211P |
Alzheimer's Disease, Frontotemporal Dementia | AD : Possible Risk Modifier, FTD : Possible Risk Modifier | Unknown; lower levels of sTREM2 in CSF of T96K/W191X/L211P carriers. | Predicted tolerated in silico by SIFT and benign by PolyPhen-2. | rs2234256 |
Coding Exon 4 |
Point, Missense CTG to CCG |
0 | Jin et al., 2015 |
W198X |
Behavioral variant FTD | FTD : Pathogenic | Unknown; frontal lobe atrophy seen on MRI. | Premature truncation. | Coding Exon 4 |
Point, Nonsense TGG to TGA |
0 | Giraldo et al., 2013 | |
A196T |
AD : Unclear Pathogenicity | Unknown. | Unknown. | Coding Exon 4 |
Point, Missense GCA to ACA |
0 | Sirkis et al., 2016 | ||
A192T |
AD : Benign | Unknown. | Predicted to be possibly damaging by Polyphen2. | rs150277350 |
Coding Exon 4 |
Point, Missense GCC to ACC |
0 | Sims et al., 2017; Jiang et al., 2016 |
|
K186N |
Nasu-Hakola Disease | NHD : Pathogenic | Brain atrophy. | Predicted to result in defects in signal transduction.
|
rs28937876 |
Coding Exon 4 |
Point, Missense AAG to AAT |
0 | Paloneva et al., 2002 |
S162R |
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown. | Normal protein maturation in HEK293 cells. | rs371702633 |
Coding Exon 4 |
Point, Missense AGC to AGG |
0 | Cuyvers et al., 2014; Sirkis et al., 2016 |
|
c.482+2T>C |
Frontotemporal Dementia, Nasu-Hakola Disease | NHD : Pathogenic, FTD : Unclear Pathogenicity | Unknown; imaging showed brain atrophy, basal ganglia calcification, and hypoperfusion in the frontotemporal cortex of NHD patient. | Exon 3 skipping, with deletion of exons 2 and/or 4, and the presence of premature or original stop codons; two truncated TREM2 protein products detected, which are likely to be nonfunctional. | rs386834144 |
Non-Coding Intron 3 |
Point |
0 | Paloneva et al., 2002; Numasawa et al., 2011 |
c.482+1G>A |
Progressive Nonfluent Aphasia | FTD : Pathogenic | Unknown; MRI showed periventricular white-matter hyperintensities, enlargement of the lateral ventricles, and thinning of the corpus callosum. | Unknown. | Non-Coding Intron 3 |
Point |
0 | Chee et al., 2017 | |
H157Y |
Alzheimer's Disease | AD : Possible Risk Modifier | Unknown. | Increases shedding of sTREM2. Reduces activation in response to phospholipid ligands and decreases phagocytosis. | rs2234255 |
Coding Exon 3 |
Point, Missense CAC to TAC |
0 | Jiang et al., 2016; Jiang et al., 2016; Sims et al., 2017 |
E151K |
AD : Benign | Unknown. | Normal protein maturation but reduction in overall expression in HEK 293 cells; when stimulated by phospholipids, reporter cells expressing the E151K variant responded similarly to cells expressing wild-type TREM2. | rs79011726 |
Coding Exon 3 |
Point, Missense GAG to AAG |
0 | Jonsson et al., 2013; Sims et al., 2017 |
|
G145W |
Probable Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown, but MRI of proband showed diffuse cortical atrophy. | Leads to a change in protein conformation (shortening of the intrinsically disordered region between the immunoglobulin-like and transmembrane domains), and reduces cellular response to activation of the TREM2/DAP12 signaling complex. | rs766647311 |
Coding Exon 3 |
Point, Missense GGG to TGG |
0 | Karsak et al., 2020 |
R136Q |
Primary Progressive Aphasia (Logopenic Variant) | AD : Benign, FTD : Unclear Pathogenicity | Unknown. | Normal protein maturation, slightly reduced cell-surface expression in HEK293 cells. | rs149622783 |
Coding Exon 3 |
Point, Missense CGG to CAG |
0 | Sims et al., 2017 |
R136W |
AD : Unclear Pathogenicity | Unknown. | Normal protein maturation, decreased total and cell-surface expression in HEK 293 cells; when stimulated by phospholipids, reporter cells expressing the R136W variant responded similarly to cells expressing wild-type TREM2. | rs772641807 |
Coding Exon 3 |
Point, Missense CGG to TGG |
0 | Jin et al., 2014 | |
D134G |
Frontotemporal Dementia, Nasu-Hakola Disease | NHD : Pathogenic, FTD : Unclear Pathogenicity | Brain atrophy. | Unknown. | rs28939079 |
Coding Exon 3 |
Point, Missense GAT to GGT |
0 | Paloneva et al., 2002 |
L133L |
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown. | Unknown. | rs144250872 |
Coding Exon 3 |
Point, Silent CTG to CTT |
0 | Cuyvers et al., 2014 | |
D131D |
AD : Benign | Not applicable. | Unknown. | rs139607688 |
Coding Exon 3 |
Point, Silent GAC to GAT |
0 | Sims et al., 2017 | |
rs7748513 |
Alzheimer's Disease | AD : Possible Risk Modifier | Unknown. | Unknown. | rs7748513 |
Non-Coding Intron 2 |
Point |
0 | Reitz et al., 2013 |
c.391+1G>A |
Frontotemporal Dementia | FTD : Pathogenic | Magnetic resonance imaging revealed cortical atrophy, ventricular enlargement, pronounced thinning of the corpus callosum, and diffuse white-matter hyperintensites. Calcification of the globus pallidus was observed by computed tomography. | In heterologous expression systems, this variant was found to cause abnormal splicing (i.e., retention of intron 2). Although TREM2 protein levels were not assayed in these in vitro studies, the lack of soluble TREM2 in the proband’s CSF suggests abnormal protein expression or processing. | Non-Coding Intron 2 |
Point |
0 | Li et al., 2019 | |
A130V |
AD : Unclear Pathogenicity | Unknown. | Predicted by SIFT to be damaging. | rs201280312 |
Coding Exon 2 |
Point, Missense GCA to GTA |
0 | Jiao et al., 2014 | |
A130S |
AD : Unclear Pathogenicity | Unknown. | Normal protein maturation when heterologously expressed in HEK293 cells. | Coding Exon 2 |
Point, Missense GCA to TCA |
0 | Sirkis et al., 2016 | ||
V126G |
Nasu-Hakola Disease | NHD : Pathogenic | Unknown; MRI showed leukoencephalopathy with sparing of arcuate fibers, cerebral atrophy, and thinning of the corpus callosum. | Poor cell-surface expression and defective for N-linked glycosylation in the Golgi. | rs121908402 |
Coding Exon 2 |
Point, Missense GTG to GGG |
0 | Klünemann et al., 2005 |
S116C |
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown. | Cell-surface expression similar to that of wild-type TREM2 heterologously expressed in HEK293 cells. | Coding Exon 2 |
Point, Missense AGT to TGT |
0 | Borroni et al., 2014 | ||
A105V |
AD : Benign | Unknown. | Unknown. | rs145080901 |
Coding Exon 2 |
Point, Missense GCG to GTG |
0 | Sims et al., 2017; Jin et al., 2015 |
|
A105T |
Primary Progressive Aphasia, Semantic Dementia | FTD : Unclear Pathogenicity | Unknown. | Predicted to be neutral by SIFT and by the PolyPhen 2 HumVar algorithm, but to be possibly damaging by PolyPhen2 HumDiv. | Coding Exon 2 |
Point, Missense GCG to ACG |
0 | Thelen et al., 2014 | |
A105RfsX84 (TREM2 313delG) |
Nasu-Hakola Disease | NHD : Pathogenic | Unknown; imaging showed cerebral atrophy, leukoencephalopathy, thinning of the corpus callosum, basal ganglia calcification. | Unknown. | rs386834141 |
Coding Exon 2 |
Deletion GCG to CGG |
0 | Klünemann et al., 2005 |
R98W |
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown. | Predicted to be probably damaging by PolyPhen2. | rs147564421 |
Coding Exon 2 |
Point, Missense CGG to TGG |
0 | Guerreiro et al., 2013 | |
T96K |
Frontotemporal Dementia | FTD : Possible Risk Modifier | Unknown; carriers of the T96K/W191X/L211P variants have lower levels of sTREM2 in CSF, compared with noncarriers. | Increased binding to cell-derived ligands and increased activation by phospholipids seen in reporter cell line. | rs2234253 |
Coding Exon 2 |
Point, Missense ACG to AAG |
0 | Thelen et al., 2014 |
G90VfsX99 (TREM2 269delG) |
Nasu-Hakola Disease | NHD : Pathogenic | Unknown; MRI showed leukoencephalopathy and cerebral atrophy. | Unknown. | rs386834140 |
Coding Exon 2 |
Deletion GGT to GTG |
0 | Klünemann et al., 2005 |
D87N |
Alzheimer's Disease | AD : Possible Risk Modifier | Typical AD pathology in single described case (Braak Stage 6). | Decreased binding to lipoproteins in cell-free assay, but increased ligand-stimulated activation in reporter cell line. | rs142232675 |
Coding Exon 2 |
Point, Missense GAT to AAT |
0 | Guerreiro et al., 2013 |
D86V |
Frontotemporal Dementia | FTD : Unclear Pathogenicity | Unknown; MRI of a patient carrying both the Y38C and D86V variants, showed cortical atrophy, thinning of the corpus callosum, periventricular white-matter abnormalities,ventricular enlargement and probable globus pallidus calcification. | Decreased cell-surface expression and defective N-linked glycosylation. | Coding Exon 2 |
Point, Missense GAC to GTC |
0 | Guerreiro et al., 2013 | |
W78X |
Nasu-Hakola Disease | NHD : Pathogenic | Brain atrophy has been reported. | Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains. | rs104893998 |
Coding Exon 2 |
Point, Nonsense TGG to TAG |
0 | Paloneva et al., 2002 |
L72V |
AD : Unclear Pathogenicity | Unknown. | Predicted by SIFT to be tolerated but by Polyphen2 to be damaging. | rs765933093 |
Coding Exon 2 |
Point, Missense CTG to GTG |
0 | Ghani et al., 2016 | |
N68K |
AD : Unclear Pathogenicity | Unknown. | Predicted benign by PolyPhen2; apparently normal protein folding. | rs753372932 |
Coding Exon 2 |
Point, Missense AAC to AAG |
0 | Guerreiro et al., 2013 | |
T66M |
Behavioral variant FTD | FTD : Pathogenic | Unknown; MRI showed frontal lobe atrophy, ventricular enlargement, and white-matter abnormalities in one homozygous carrier, and frontal and parietal lobe atrophy in two other homozygous carriers. | Greatly decreased cell-surface expression and shedding of sTREM2, reduced ligand binding, and impaired phagocytosis. | rs201258663 |
Coding Exon 2 |
Point, Missense ACG to ATG |
1 | Guerreiro et al., 2013 |
R62H |
Alzheimer's Disease | AD : Risk Modifier | AD patients heterozygous for the R62H variant: decreased microglial coverage of amyloid plaques and increased accumulation of phagosomes in microglia, compared to non-carriers. | Decreased ligand binding to TREM2 and impaired TREM2-mediated activation. | rs143332484 |
Coding Exon 2 |
Point, Missense CGT to CAT |
0 | Jin et al., 2014; Sims et al., 2017 |
R62C |
AD : Unclear Pathogenicity | Unknown. | Lower cell-surface expression than wild-type TREM2 when co-expressed with its adaptor protein DAP12 in a reporter cell line; activation by lipid ligands reduced in cells expressing R62C compared with cells expressing wild-type TREM2. | rs201258314 |
Coding Exon 2 |
Point, Missense CGT to TGT |
0 | Pottier et al., 2013; Song et al., 2017 |
|
G58A |
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown. | Predicted by Polyphen2 to be probably damaging, by SIFT to be tolerated, and by SNPs&Go to be neutral. | Coding Exon 2 |
Point, Missense GGC to GCC |
0 | Cuyvers et al., 2014 | ||
R52H |
AD : Unclear Pathogenicity | Unknown. | Lower cell-surface expression than wild-type TREM2 when co-expressed with its adaptor protein DAP12 in a reporter cell line, but activation by phospholipids similar in cells expressing R52H and wild-type TREM2. | rs374851046 |
Coding Exon 2 |
Point, Missense CGC to CAC |
0 | Jin et al., 2014 | |
R52C |
Behavioral variant FTD | FTD : Unclear Pathogenicity | MRI showed diffuse brain atrophy and ventricular enlargement. | Unknown. | rs749358844 |
Coding Exon 2 |
Point, Missense CGC to TGC |
0 | Soares et al., 2020 |
R47H |
Alzheimer's Disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease | AD : Risk Modifier, FTD : Possible Risk Modifier, PD : Possible Risk Modifier, ALS : Possible Risk Modifier | AD patients heterozygous for the R47H variant: generally typical AD pathology, but subtle differences compared to non-carriers, including decreased microglial coverage of amyloid plaques and accumulation of phagosomes in microglia. | Decreased ligand binding to TREM2 and impaired TREM2-mediated activation. | rs75932628 |
Coding Exon 2 |
Point, Missense CGC to CAC |
24 | Guerreiro et al., 2013; Jonsson et al., 2013 |
R47C |
Behavioral variant FTD | AD : Unclear Pathogenicity, FTD : Pathogenic | Unknown, but MRI showed symmetric frontal and temporal lobe atrophy in homozygous carrier. | Normal protein maturation, decreased total and cell-surface expression in HEK293 cells. | rs753325601 |
Coding Exon 2 |
Point, Missense CGC to TGC |
0 | Sirkis et al., 2016; Ng et al., 2018 |
G45E |
AD : Unclear Pathogenicity | Unknown. | Unknown. | Coding Exon 2 |
Point, Missense GGG to GAG |
0 | Jonsson et al., 2013 | ||
W44X |
Nasu-Hakola Disease | NHD : Pathogenic | Brain atrophy reported. | Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains. | rs104894001 |
Coding Exon 2 |
Point, Nonsense TGG to TGA |
0 | Paloneva et al., 2002 |
H43Y |
AD : Unclear Pathogenicity | Unknown. | Predicted benign by PolyPhen2. | Coding Exon 2 |
Point, Missense CAC to TAC |
0 | Pottier et al., 2013 | ||
D39E |
AD : Benign, FTD : Unclear Pathogenicity | Not applicable. | Predicted to be possibly damaging by Polyphen-2, but to be tolerated by SIFT and neutral by SNPs&Go. | rs200392967 |
Coding Exon 2 |
Point, Missense GAC to GAG |
0 | Sims et al., 2017 | |
D39G |
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown. | Predicted to be benign by Polyphen-2, tolerated by SIFT, and neutral by SNPs&Go. | Coding Exon 2 |
Point, Missense GAC to GGC |
0 | Cuyvers et al., 2014 | ||
Y38C |
Frontotemporal Dementia | FTD : Pathogenic | Unknown; MRI shows cortical atrophy and white matter abnormalities. | Alters post-translational processing of TREM2, ligand binding, and TREM2-mediated phagocytosis. | rs797044603 |
Coding Exon 2 |
Point, Missense TAT to TGT |
1 | Guerreiro et al., 2013 |
Q33X |
Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease | NHD : Pathogenic, FTD : Pathogenic, AD : Possible Risk Modifier | Unknown for homozygous carriers; MRI showed cerebral atrophy. Heterozygous AD patient showed typical AD pathology. | Loss of TREM2 expression. | rs104894002 |
Coding Exon 2 |
Point, Nonsense CAG to TAG |
0 | Soragna et al., 2003; Guerreiro et al., 2013 |
S31F |
AD : Unclear Pathogenicity | Unknown. | Normal protein maturation, decreased total and cell-surface expression in HEK293 cells. | rs746216516 |
Coding Exon 2 |
Point, Missense TCC to TTC |
0 | Sirkis et al., 2016 | |
A28V |
Primary Progressive Aphasia, Progressive Nonfluent Aphasia | AD : Benign, FTD : Unclear Pathogenicity | Unknown. | Normal protein maturation and increased cell-surface expression in HEK293 cells. | rs2234252 |
Coding Exon 2 |
Point, Missense GCG to GTG |
0 | Sims et al., 2017 |
V27M |
AD : Unclear Pathogenicity | Unknown. | Normal protein maturation in HEK293 cells. | rs768745050 |
Coding Exon 2 |
Point, Missense GTG to ATG |
0 | Sirkis et al., 2016 | |
G17E |
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity | Unknown. | Predicted benign by Polyphen-2, tolerated by SIFT, neutral by SNPs&Go. | Coding Exon 2 |
Point, Missense GGA to GAA |
0 | Cuyvers et al., 2014 | ||
S16F |
AD : Unclear Pathogenicity | Unknown. | Unknown. | rs777808487 |
Coding Exon 2 |
Point, Missense TCC to TTC |
0 | Sirkis et al., 2016 | |
c.40+3 delAGG |
Frontotemporal Dementia | FTD : Pathogenic | Unknown; MRI showed brain atrophy, including thinning of the corpus callosum. | Reduction in the level of TREM2 transcripts. | Non-Coding Intron 1 |
Deletion |
0 | Chouery et al., 2008 | |
E14X |
Nasu-Hakola Disease | NHD : Pathogenic | Unknown. | Premature truncation codon; no transcripts detected. | rs386834143 |
Coding Exon 1 |
Point, Nonsense GAG to TAG |
0 | Paloneva et al., 2003 |
rs7748777 |
Alzheimer's Disease, ~ 1 year follow-up | AD : Possible Risk Modifier | Unknown. | Unknown. | rs7748777 |
Non-Coding Upstream |
Point |
0 | Wang et al., 2015 |
rs7759295 |
AD : Unclear Pathogenicity | This variant was associated with a higher burden of neurofibrillary tangles in subjects from three prospective cohort studies, but not with amyloid plaques, amyloid angiopathy, Lewy body pathology, terminally activated microglia, or cerebral infarcts. | Unknown. | rs7759295 |
Non-Coding Upstream |
Point |
0 | Replogle et al., 2015 | |
rs9357347 |
Alzheimer's Disease | AD : Possible Risk Modifier | Unknown. | Predicted to influence transcription factor binding; 6 percent increase in expression of TREM2 and TREML1 in temporal cortex. | rs9357347 |
Non-Coding Intergenic - TREM locus |
Point |
0 | Carrasquillo et al., 2017 |
W50C |
Nasu-Hakola Disease | NHD : Pathogenic | Unknown; imaging showed brain atrophy, diffuse white-matter hyperintensities, thinning of the corpus callosum, and basal ganglia calcification. | Unknown; predicted to be harmful in silico by Polyphen-2 and SIFT. | Coding Exon 2 |
Point, Missense GAG to TAG |
0 | Dardiotis et al., 2017 |