Is TREM2 p.Pro59Ala (c.175C>G) pathogenic?

TREM2 p.Pro59Ala (c.175C>G) is classified Uncertain significance in TREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-17). AlphaMissense: likely benign (0.0818); Very rare (popmax 8.47e-05%, nfe).

How common is TREM2 p.Pro59Ala (c.175C>G) in the general population?

TREM2 p.Pro59Ala (c.175C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TREM2 p.Pro59Ala (c.175C>G)?

AlphaMissense predicts likely benign (score 0.0818) — an in-silico prediction, not a clinical call.

TREM2 p.Pro59Ala

c.175C>G · rs2532388475 · VCV1935382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0818	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	phastCons 0.96
Regional constraint	o/e 0.92	unconstrained · MANE · 4,315 bp · p 0.2 · regional, not allelic
Overall
CADD	9.393	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.19e-05% 1/1,614,210 alleles · very rare exomes 1/1,461,888 · genomes 0/152,322 · joint denominator

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.Pro59Ala
Coding: c.175C>G
MANE Select: NM_018965
dbSNP: rs2532388475
Type: single nucleotide variant
Location: chr6:41161479 (GRCh38)
Gene constraint: LOEUF 1.211 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.85 · 15 PDB
Residue 59: 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); the ig-like v-type domain

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

Similar variants

TREM2 p.Pro59Gln Uncertain significance ★ ⚠ same residue
TREM2 c.483-2A>C Likely pathogenic ★★ same type
TREM2 p.Asp86Val Likely pathogenic ★★ same type
TREM2 p.Gln33Ter Pathogenic ★★ same type
TREM2 p.Thr66Met Pathogenic/Likely pathogenic ★★ same type
TREM2 p.Val126Gly Pathogenic/Likely pathogenic ★★ same type
TREM2 c.-51G>A Uncertain significance ★★ same type
TREM2 c.-98C>T Uncertain significance ★★ same type

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-pro59ala (accessed [today's date]).

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