Is TRIM2 p.Arg166Gln (c.497G>A) pathogenic?

TRIM2 p.Arg166Gln (c.497G>A) is classified Uncertain significance in TRIM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.0647); Very rare (popmax 0.00729%, nfe); Associated with Charcot-Marie-Tooth disease type 2R.

What condition is associated with TRIM2 p.Arg166Gln (c.497G>A)?

TRIM2 p.Arg166Gln (c.497G>A) is associated with Charcot-Marie-Tooth disease type 2R (ClinVar).

How common is TRIM2 p.Arg166Gln (c.497G>A) in the general population?

TRIM2 p.Arg166Gln (c.497G>A) is very rare (popmax 0.00729%, nfe) (gnomAD).

How is Charcot-Marie-Tooth disease type 2R inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TRIM2 p.Arg166Gln (c.497G>A)?

AlphaMissense predicts likely benign (score 0.0647) — an in-silico prediction, not a clinical call.

TRIM2 p.Arg166Gln

c.497G>A · rs146252965 · VCV474609

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00729%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 2R

Computational evidence

Protein change
AlphaMissense	0.0647	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.88	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 4	GERP 1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 124 kb · p 1.1e-19 · regional, not allelic
Overall
CADD	20.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R139Q vs ClinVar R166Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00729% European (non-Finnish) · 86/1,179,500 alleles

Filtering AF 0.00604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.00595% 96/1,613,196 alleles · very rare exomes 86/1,461,032 · genomes 10/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00729%	13,715
East Asian	0.00668%	14,959
Remaining individualsnot grpmax-eligible	0.0048%	20,814
African / African-American	0.00267%	37,447
South Asian	0.0022%	45,488

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: TRIM2
Protein: p.Arg166Gln
Coding: c.497G>A
MANE Select: NM_015271
dbSNP: rs146252965
Type: single nucleotide variant
Location: chr4:153293025 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.91 · 6 PDB

Full TRIM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 2R — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Charcot-Marie-Tooth disease type 2R (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

TRIM2 p.Arg166Trp Uncertain significance ★★ ⚠ same residue
TRIM2 p.Ala139Val Uncertain significance ★★ ⚠ same condition
TRIM2 p.Ala174Thr Uncertain significance ★★ ⚠ same condition
TRIM2 p.Ala225Ser Uncertain significance ★★ ⚠ same condition
TRIM2 p.Ala225Thr Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg245His Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg321Gln Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg41Cys 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/trim2-p-arg166gln (accessed [today's date]).

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