TREM2

Chr 6AR

triggering receptor expressed on myeloid cells 2

Also known as: AD17, PLOSL2, TREM-2, Trem2a, Trem2b, Trem2c

NCBI Gene: 54209ENSG00000095970UniProt: Q9NZC2

This gene encodes a membrane protein that forms a receptor signaling complex with the TYRO protein tyrosine kinase binding protein. The encoded protein functions in immune response and may be involved in chronic inflammation by triggering the production of constitutive inflammatory cytokines. Defects in this gene are a cause of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]

Primary Disease Associations & Inheritance

{Alzheimer disease 17, susceptibility to}MIM #615080
AR
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2MIM #618193
AR
196
ClinVar variants
32
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— TREM2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 78 VUS of 196 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.79LOEUF
pLI 0.000
Z-score -0.52
OE 1.17 (0.75–1.79)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.24Z-score
OE missense 0.94 (0.81–1.09)
125 obs / 132.9 exp
Tolerant

Mild missense constraint

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.1.17 (0.75–1.79)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.81–1.09)
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.0.79
0≤1.21.6
LoF obs/exp: 12 / 10.2Missense obs/exp: 125 / 132.9Syn Z: 1.27

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic14
VUS78
Likely Benign70
Benign3
Conflicting13
18
Pathogenic
14
Likely Pathogenic
78
VUS
70
Likely Benign
3
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
1
12
0
18
Likely Pathogenic
7
3
4
0
14
VUS
0
71
4
3
78
Likely Benign
0
10
24
36
70
Benign
0
1
2
0
3
Conflicting
—13
Total12864639196

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

View in ClinVar →

Protein Context — Lollipop Plot

TREM2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Alzheimer disease 17, susceptibility to}

MIM #615080

Molecular basis of disorder known

Autosomal recessive

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

MIM #618193

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TREM2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.
Krasemann S et al.·Immunity
2017Functional
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.
Zhou Y et al.·Nat Med
2020Functional
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways.
Wang S et al.·Cell
2022
Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model.
Wang S et al.·J Exp Med
2020Clinical trial
TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge.
Nugent AA et al.·Neuron
2020
Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages.
Obradovic A et al.·Cell
2021
Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis.
Mocci G et al.·Circ Res
2024
TREM2 Depletion in Pancreatic Cancer Elicits Pathogenic Inflammation and Accelerates Tumor Progression via Enriching IL-1β(+) Macrophages.
Yang D et al.·Gastroenterology
2025
TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity.
Cui H et al.·Nat Commun
2025
Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.
Wang X et al.·Immunity
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Subjective Cognitive Decline (SCD)Subjective Cognitive Complaints (SCCs)Subjective Cognitive Impairment

The Signature of Alzheimer's Disease in Subjective Cognitive Decline

RECRUITING
NCT07402161IRCCS Policlinico S. DonatoStarted 2025-10-01
Cerebral Amyloid Aβ Angiopathy

Phenotypic and Molecular Characterisation of Cerebral Amyloid Angiopathy

RECRUITING
NCT06864000University Hospital, RouenStarted 2023-03-31

External Resources

Links to major genomics databases and tools