Is TRIM2 p.Ala656Ser (c.1966G>T) pathogenic?

TRIM2 p.Ala656Ser (c.1966G>T) is classified Uncertain significance in TRIM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). AlphaMissense: ambiguous (0.3426); Very rare (popmax 0.000424%, nfe); Associated with Charcot-Marie-Tooth disease type 2R.

What condition is associated with TRIM2 p.Ala656Ser (c.1966G>T)?

TRIM2 p.Ala656Ser (c.1966G>T) is associated with Charcot-Marie-Tooth disease type 2R (ClinVar).

How common is TRIM2 p.Ala656Ser (c.1966G>T) in the general population?

TRIM2 p.Ala656Ser (c.1966G>T) is very rare (popmax 0.000424%, 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.Ala656Ser (c.1966G>T)?

AlphaMissense predicts ambiguous (score 0.3426) — an in-silico prediction, not a clinical call.

TRIM2 p.Ala656Ser

c.1966G>T · VCV3690120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3426 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Charcot-Marie-Tooth disease type 2R

Computational evidence

Protein change
AlphaMissense	0.3426	ambiguous
REVEL	0.581	indeterminate
SaProt	LLR -8.40	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.26	loss · gain 0.00 · not in the SpliceAI release · independent
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	28.6	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 A629S vs ClinVar A656S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,408 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000411% 6/1,460,058 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,840
European (non-Finnish)grpmax	0.000424%	235,881

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala656Ser
Coding: c.1966G>T
MANE Select: NM_015271
Type: single nucleotide variant
Location: chr4:153324092 (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 629 UniProt numbering: a β-strand

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.Ala656Asp 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-ala656ser (accessed [today's date]).

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