# NM_018006.5(TRMU):c.524T>C (p.Phe175Ser)

https://sugi.bio/variant/trmu-p-phe175ser

## Summary

**TRMU p.Phe175Ser (c.524T>C)** is classified **Uncertain significance** in TRMU (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). AlphaMissense: likely pathogenic (0.9094); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs747567710 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the TRMU gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [TRMU](https://sugi.bio/atlas/gene/TRMU/) |
| Protein change (HGVS p.) | p.Phe175Ser |
| Coding change (HGVS c.) | c.524T>C |
| MANE Select transcript | [NM_018006](https://www.ncbi.nlm.nih.gov/nuccore/NM_018006) |
| dbSNP | [rs747567710](https://www.ncbi.nlm.nih.gov/snp/rs747567710/) |
| Variant type | single nucleotide variant |
| Location | chr22:46350336-46350336 (GRCh38) |
| ClinVar | [VCV2227328](https://www.ncbi.nlm.nih.gov/clinvar/variation/2227328/) |

**All HGVS expressions:** `NC_000022.10:g.46746233T>C`, `NC_000022.11:g.46350336T>C`, `NG_012173.1:g.19936T>C`, `NM_001282782.2:c.182T>C`, `NM_001282783.2:c.118-14T>C`, `NM_001282784.2:c.118-14T>C`, `NM_001282785.2:c.524T>C`, `NM_018006.5:c.524T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9094)
- REVEL 0.895 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.898 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.39) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.677, GERP 1.1, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 1.07** across the covering region of the MANE Select transcript (46,335,765–46,357,003), spanning 21,238 bp. Chi-square p 0.086. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.39**, donor loss **0.00**, acceptor gain **0.08**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.39**, donor loss **0.00**, acceptor gain **0.08**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000763% · FAF99 0.000605% · 1/44,896 in the highest group · 19/1,614,122 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,896 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| African / African-American | 0.00133% | 74,950 |
| European (non-Finnish) | 0.00127% | 78,670 |
| South Asian | 0.0011% | 91,094 |

*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}

**TRMU** population constraint: LOEUF 1.276, pLI 2.8114e-17, missense-Z -0.36829; 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.*

Curated gene–disease validity (ClinGen):

- **mitochondrial disease** — Definitive (AR)
- **Leigh syndrome** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.60, 78% of residues very-high.

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

*Describes the biological roles of TRMU (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [tRNA modification in the mitochondrion](https://reactome.org/content/detail/R-HSA-6787450) | electronic |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-28 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related TRMU variant pages (same residue, condition, or type): [TRMU p.Phe175=](/variant/trmu-p-phe175), [TRMU p.Ala268Thr](/variant/trmu-p-ala268thr), [TRMU p.Arg26Gln](/variant/trmu-p-arg26gln), [TRMU p.Arg306Ser](/variant/trmu-p-arg306ser), [TRMU p.Arg309Cys](/variant/trmu-p-arg309cys), [TRMU p.Arg385Trp](/variant/trmu-p-arg385trp), [TRMU p.Cys222Tyr](/variant/trmu-p-cys222tyr), [TRMU p.Cys377Trp](/variant/trmu-p-cys377trp).

### 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 2227328). 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.*