Is TRIM2 p.Leu253= (c.757T>C) pathogenic?

TRIM2 p.Leu253= (c.757T>C) is classified Likely benign in TRIM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.0167%, amr); Associated with Charcot-Marie-Tooth disease type 2R.

What condition is associated with TRIM2 p.Leu253= (c.757T>C)?

TRIM2 p.Leu253= (c.757T>C) is associated with Charcot-Marie-Tooth disease type 2R (ClinVar).

How common is TRIM2 p.Leu253= (c.757T>C) in the general population?

TRIM2 p.Leu253= (c.757T>C) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

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

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

TRIM2 p.Leu253=

c.757T>C · rs748899501 · VCV1134675

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Conditions

Charcot-Marie-Tooth disease type 2R

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 1.8	GERP -0.039, phastCons 0.97
Overall
CADD	8.652	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,984 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00149% 24/1,613,844 alleles · ultra-rare exomes 13/1,461,724 · genomes 11/152,120 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,998
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00267%	37,446
South Asian	0.0022%	45,515
European (non-Finnish)	0.000508%	196,659

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.Leu253=
Coding: c.757T>C
MANE Select: NM_015271
dbSNP: rs748899501
Type: single nucleotide variant
Location: chr4:153294456 (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.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.Arg166Gln Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg166Trp Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg245His Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg321Gln 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-leu253 (accessed [today's date]).

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