# NM_020810.3(TRMT5):c.306G>A (p.Arg102=)

https://sugi.bio/variant/trmt5-p-arg102

## Summary

**TRMT5 p.Arg102= (c.306G>A)** is classified **Likely benign** in TRMT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-14). Very rare (popmax 0.00167%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs1261461753 · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the TRMT5 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRMT5](https://sugi.bio/atlas/gene/TRMT5/) |
| Protein change (HGVS p.) | p.Arg102= |
| Coding change (HGVS c.) | c.306G>A |
| MANE Select transcript | [NM_020810](https://www.ncbi.nlm.nih.gov/nuccore/NM_020810) |
| dbSNP | [rs1261461753](https://www.ncbi.nlm.nih.gov/snp/rs1261461753/) |
| Variant type | single nucleotide variant |
| Location | chr14:60979592-60979592 (GRCh38) |
| ClinVar | [VCV1984337](https://www.ncbi.nlm.nih.gov/clinvar/variation/1984337/) |

**All HGVS expressions:** `NC_000014.8:g.61446310C>T`, `NC_000014.9:g.60979592C>T`, `NG_053119.1:g.7099G>A`, `NM_001350253.1:c.390G>A`, `NM_001350254.1:c.387G>A`, `NM_020810.3:c.306G>A`

## 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 0.261, GERP -1.7, phastCons 0.012 — weakly conserved position
- CADD: **PHRED 8.128**. 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 (C>A, Δ0.35 donor gain), 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 **0.00167%** (amr) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/60,002 in the highest group · 4/1,614,150 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,002 |
| European (non-Finnish) | 0.000254% | 393,342 |

*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}

**TRMT5** population constraint: LOEUF 0.969, pLI 9.3056e-09, missense-Z 0.79761. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.50, 64% of residues very-high.

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

*Describes the biological roles of TRMT5 (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}

TRMT5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of wybutosine at G37 of tRNA(Phe)](https://reactome.org/content/detail/R-HSA-6782861) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** mitochondrial tRNA methylation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-14.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-14 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related TRMT5 variant pages (same residue, condition, or type): [TRMT5 p.Ala188Asp](/variant/trmt5-p-ala188asp), [TRMT5 p.Ala45Thr](/variant/trmt5-p-ala45thr), [TRMT5 p.Ala45Val](/variant/trmt5-p-ala45val), [TRMT5 p.Arg120Cys](/variant/trmt5-p-arg120cys), [TRMT5 p.Arg125His](/variant/trmt5-p-arg125his), [TRMT5 p.Arg15Thr](/variant/trmt5-p-arg15thr), [TRMT5 p.Arg266Gln](/variant/trmt5-p-arg266gln), [TRMT5 p.Arg291His](/variant/trmt5-p-arg291his).

### 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 1984337). 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.*