Is TREM2 p.Asp131= (c.393C>T) pathogenic?

TREM2 p.Asp131= (c.393C>T) is classified Conflicting classifications of pathogenicity in TREM2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-28). Very rare (popmax 0.0067%, nfe); Associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2.

How common is TREM2 p.Asp131= (c.393C>T) in the general population?

TREM2 p.Asp131= (c.393C>T) is very rare (popmax 0.0067%, nfe) (gnomAD).

TREM2 p.Asp131=

Q: What condition is associated with TREM2 p.Asp131= (c.393C>T)?

TREM2 p.Asp131= (c.393C>T) is associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 (ClinVar).

c.393C>T · rs139607688 · VCV356677

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0067%, nfe)

Conditions

polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	phastCons 1
Overall
CADD	4.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0067% European (non-Finnish) · 79/1,179,824 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00552% 89/1,613,476 alleles · very rare exomes 81/1,461,288 · genomes 8/152,188 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,941
European (non-Finnish)grpmax	0.0067%	14,934
Finnishnot grpmax-eligible	0.00157%	63,768

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TREM2
Protein: p.Asp131=
Coding: c.393C>T
MANE Select: NM_018965
dbSNP: rs139607688
Type: single nucleotide variant
Location: chr6:41159881 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.85 · 15 PDB
Residue 131: a UniProt-annotated variant site (in plosl2; results in decreased osteoclast differentiation; no trem2 transcripts can be detected in patient cells homozygous for the variant); a UniProt-annotated variant site (in plosl2; complete loss of protein expression); a UniProt-annotated variant site (in plosl2)

Full TREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TREM2 p.Asp86Val Likely pathogenic ★★ same condition
TREM2 p.Gln33Ter Pathogenic ★★ same condition
TREM2 p.Thr66Met Pathogenic/Likely pathogenic ★★ same condition
TREM2 p.Val126Gly Pathogenic/Likely pathogenic ★★ same condition
TREM2 c.-51G>A Uncertain significance ★★ same condition
TREM2 c.-98C>T Uncertain significance ★★ same condition
TREM2 c.*148C>T Uncertain significance ★★ same condition
TREM2 c.*156G>T Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/trem2-p-asp131 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown