# NM_015271.5(TRIM2):c.2169T>C (p.Phe723=)

https://sugi.bio/variant/trim2-p-phe723

## Summary

**TRIM2 p.Phe723= (c.2169T>C)** is classified **Likely benign** in TRIM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-11). Ultra-rare (popmax 0.0497%, sas); Associated with Charcot-Marie-Tooth disease type 2R.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs148412849 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0497%, sas)

## For patients & families {#patients}

This is a change in the TRIM2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Charcot-Marie-Tooth disease type 2R.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TRIM2 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012451/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRIM2](https://sugi.bio/atlas/gene/TRIM2/) |
| Protein change (HGVS p.) | p.Phe723= |
| Coding change (HGVS c.) | c.2169T>C |
| MANE Select transcript | [NM_015271](https://www.ncbi.nlm.nih.gov/nuccore/NM_015271) |
| dbSNP | [rs148412849](https://www.ncbi.nlm.nih.gov/snp/rs148412849/) |
| Variant type | single nucleotide variant |
| Location | chr4:153334819-153334819 (GRCh38) |
| ClinVar | [VCV541518](https://www.ncbi.nlm.nih.gov/clinvar/variation/541518/) |

**All HGVS expressions:** `NC_000004.11:g.154255971T>C`, `NC_000004.12:g.153334819T>C`, `NG_041788.1:g.186702T>C`, `NM_001130067.2:c.2088T>C`, `NM_001351054.2:c.2154T>C`, `NM_001351055.2:c.2151T>C`, `NM_001351056.2:c.2100T>C`, `NM_001351057.2:c.1713T>C`, `NM_015271.5:c.2169T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.891, GERP -0.54, phastCons 1 — weakly conserved position
- CADD: **PHRED 5.855**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.22 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0497%** (sas) · FAF95 0.0381% · FAF99 0.0341% · 45/90,570 in the highest group · 108/1,610,900 alleles overall — ultra-rare (popmax 0.0497%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0497% | 2,013 |
| Middle Eastern | 0.0165% | 6,070 |
| European (non-Finnish) | 0.00484% | 20,666 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,791 |
| East Asian | 0.00223% | 44,824 |
| Admixed American | 0.00167% | 59,782 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TRIM2** population constraint: LOEUF 0.398, pLI 0.99998, missense-Z 3.9511; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.91, 55% of residues very-high.

**6 experimental structure(s)** (PDB): [7B2R](https://www.rcsb.org/structure/7B2R), [7B96](https://www.rcsb.org/structure/7B96), [7QRV](https://www.rcsb.org/structure/7QRV), [7ZJ3](https://www.rcsb.org/structure/7ZJ3), [8A38](https://www.rcsb.org/structure/8A38), [8AMS](https://www.rcsb.org/structure/8AMS).

## What this gene does {#gene-function}

*Describes the biological roles of TRIM2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

TRIM2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | other |

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-11.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-11 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-18 |

## Associated conditions {#conditions}

[Charcot-Marie-Tooth disease type 2R](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-2r/).

**Reported phenotype names (ClinVar):** Charcot-Marie-Tooth disease type 2R, not specified, CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2R, Charcot-Marie-Tooth disease, axonal, type 2R, CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2R, AllHighlyPenetrant.

## Similar variants {#similar}

Related TRIM2 variant pages (same residue, condition, or type): [TRIM2 p.Ala139Val](/variant/trim2-p-ala139val), [TRIM2 p.Ala174Thr](/variant/trim2-p-ala174thr), [TRIM2 p.Ala225Ser](/variant/trim2-p-ala225ser), [TRIM2 p.Ala225Thr](/variant/trim2-p-ala225thr), [TRIM2 p.Arg166Gln](/variant/trim2-p-arg166gln), [TRIM2 p.Arg166Trp](/variant/trim2-p-arg166trp), [TRIM2 p.Arg245His](/variant/trim2-p-arg245his), [TRIM2 p.Arg321Gln](/variant/trim2-p-arg321gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 541518). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*