Is TRIM2 p.Pro468Ser (c.1402C>T) pathogenic?

TRIM2 p.Pro468Ser (c.1402C>T) is classified Uncertain significance in TRIM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-18). AlphaMissense: likely pathogenic (0.5736); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease type 2R.

What condition is associated with TRIM2 p.Pro468Ser (c.1402C>T)?

TRIM2 p.Pro468Ser (c.1402C>T) is associated with Charcot-Marie-Tooth disease type 2R (ClinVar).

How common is TRIM2 p.Pro468Ser (c.1402C>T) in the general population?

TRIM2 p.Pro468Ser (c.1402C>T) is absent from gnomAD v4.1 (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.Pro468Ser (c.1402C>T)?

AlphaMissense predicts likely pathogenic (score 0.5736) — an in-silico prediction, not a clinical call.

TRIM2 p.Pro468Ser

c.1402C>T · rs2067279323 · VCV1716884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5736 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 2R

Computational evidence

Protein change
AlphaMissense	0.5736	likely pathogenic
REVEL	0.376	indeterminate
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 124 kb · p 1.1e-19 · regional, not allelic
Overall
CADD	26.1	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 P441S vs ClinVar P468S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRIM2
Protein: p.Pro468Ser
Coding: c.1402C>T
MANE Select: NM_015271
dbSNP: rs2067279323
Type: single nucleotide variant
Location: chr4:153295928 (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 441 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.Pro468Leu 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.Arg166Gln Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg166Trp Uncertain significance ★★ ⚠ same condition
TRIM2 p.Arg245His 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-pro468ser (accessed [today's date]).

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