Is TRIM2 p.Pro739Ser (c.2215C>T) pathogenic?

TRIM2 p.Pro739Ser (c.2215C>T) is classified Uncertain significance in TRIM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: likely pathogenic (0.9339); Rare (popmax 0.171%, afr); Associated with Charcot-Marie-Tooth disease type 2R.

What condition is associated with TRIM2 p.Pro739Ser (c.2215C>T)?

TRIM2 p.Pro739Ser (c.2215C>T) is associated with Charcot-Marie-Tooth disease type 2R (ClinVar).

How common is TRIM2 p.Pro739Ser (c.2215C>T) in the general population?

TRIM2 p.Pro739Ser (c.2215C>T) is rare (popmax 0.171%, afr) (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.Pro739Ser (c.2215C>T)?

AlphaMissense predicts likely pathogenic (score 0.9339) — an in-silico prediction, not a clinical call.

TRIM2 p.Pro739Ser

c.2215C>T · rs199912457 · VCV653645

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9339 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.171%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 2R

Computational evidence

Protein change
AlphaMissense	0.9339	likely pathogenic
REVEL	0.429	indeterminate
SaProt	LLR -8.12	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 0.40	unconstrained · MANE · 6,398 bp · p 2.2e-09 · regional, not allelic
Overall
CADD	28.5	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 P712S vs ClinVar P739S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.171% African / African-American · 128/75,036 alleles

Filtering AF 0.146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.0102% 165/1,613,934 alleles · rare exomes 108/1,461,666 · genomes 57/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.171%	586
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.0117%	8,567
South Asian	0.0033%	30,347
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.000339%	294,974

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.Pro739Ser
Coding: c.2215C>T
MANE Select: NM_015271
dbSNP: rs199912457
Type: single nucleotide variant
Location: chr4:153334865 (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-pro739ser (accessed [today's date]).

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