Is TRIM2 p.Arg464His (c.1391G>A) pathogenic?

TRIM2 p.Arg464His (c.1391G>A) is classified Uncertain significance in TRIM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-17). AlphaMissense: ambiguous (0.4622); Very rare (popmax 0.00169%, amr); Associated with Charcot-Marie-Tooth disease type 2R.

What condition is associated with TRIM2 p.Arg464His (c.1391G>A)?

TRIM2 p.Arg464His (c.1391G>A) is associated with Charcot-Marie-Tooth disease type 2R (ClinVar).

How common is TRIM2 p.Arg464His (c.1391G>A) in the general population?

TRIM2 p.Arg464His (c.1391G>A) is very rare (popmax 0.00169%, 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.

What do computational predictors say about TRIM2 p.Arg464His (c.1391G>A)?

AlphaMissense predicts ambiguous (score 0.4622) — an in-silico prediction, not a clinical call.

TRIM2 p.Arg464His

c.1391G>A · rs1235210272 · VCV1364772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Conditions

Charcot-Marie-Tooth disease type 2R

Computational evidence

Protein change
AlphaMissense	0.4622	ambiguous
REVEL	0.439	indeterminate
SaProt	LLR -7.43	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 124 kb · p 1.1e-19 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R437H vs ClinVar R464H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% Admixed American · 1/59,320 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.00106% 17/1,609,280 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,320
Remaining individualsnot grpmax-eligible	0.00161%	62,298
African / African-American	0.00134%	74,774
South Asian	0.00111%	90,292
European (non-Finnish)	0.0011%	90,593

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.Arg464His
Coding: c.1391G>A
MANE Select: NM_015271
dbSNP: rs1235210272
Type: single nucleotide variant
Location: chr4:153295917 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.91 · 6 PDB
Residue 437 UniProt numbering: the 'disordered' region

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.Arg464Cys Uncertain significance ★ ⚠ same residue
TRIM2 p.Arg464= Likely benign ★ 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.Arg166Gln Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg166Trp 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-arg464his (accessed [today's date]).

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