# NM_006073.4(TRDN):c.2037C>T (p.Pro679=)

https://sugi.bio/variant/trdn-p-pro679

## Summary

**TRDN p.Pro679= (c.2037C>T)** is classified **Likely benign** in TRDN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). Very rare (popmax 0.00273%, afr); Associated with catecholaminergic polymorphic ventricular tachycardia 1.

**At a glance:** Likely benign · review: Single submitter · rsID rs1288875041 · 1 submitter · 1 linked condition · very rare (popmax 0.00273%, afr)

## For patients & families {#patients}

This is a change in the TRDN gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to catecholaminergic polymorphic ventricular tachycardia 1.

*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 dominant |
| Age of onset (of this condition) | No data available |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TRDN is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024803/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRDN](https://sugi.bio/atlas/gene/TRDN/) |
| Protein change (HGVS p.) | p.Pro679= |
| Coding change (HGVS c.) | c.2037C>T |
| MANE Select transcript | [NM_006073](https://www.ncbi.nlm.nih.gov/nuccore/NM_006073) |
| dbSNP | [rs1288875041](https://www.ncbi.nlm.nih.gov/snp/rs1288875041/) |
| Variant type | single nucleotide variant |
| Location | chr6:123221500-123221500 (GRCh38) |
| ClinVar | [VCV1900402](https://www.ncbi.nlm.nih.gov/clinvar/variation/1900402/) |

**All HGVS expressions:** `NC_000006.11:g.123542645G>A`, `NC_000006.12:g.123221500G>A`, `NG_030438.1:g.420594C>T`, `NM_006073.4:c.2037C>T`

## 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 -0.154, GERP -0.252, phastCons 0.003 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 3.938**. 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 (G>C, Δ0.20 acceptor 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 **0.00273%** (afr) · FAF95 0.000453% · FAF99 0.000169% · 2/73,342 in the highest group · 2/1,567,858 alleles overall — very rare (popmax 0.00273%, afr).

*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}

**TRDN** population constraint: LOEUF 1.359, pLI 1.1258e-24, missense-Z -1.0725; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **long QT syndrome** — Strong (AR)
- **catecholaminergic polymorphic ventricular tachycardia** — Definitive (AR)

## Protein context {#protein}

Residue **679** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 47.65, 2% of residues very-high.

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

*Describes the biological roles of TRDN (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}

TRDN participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

**Biological process:** heart contraction.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-01.

**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 | 2022-07-01 |

## Associated conditions {#conditions}

[catecholaminergic polymorphic ventricular tachycardia 1](https://sugi.bio/atlas/disease/catecholaminergic-polymorphic-ventricular-tachycardia-1/).

**Reported phenotype names (ClinVar):** Catecholaminergic polymorphic ventricular tachycardia 1, RYR2-Related Catecholaminergic Polymorphic Ventricular Tachycardia, VENTRICULAR TACHYCARDIA, STRESS-INDUCED POLYMORPHIC 1, VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND/OR DILATED CARDIOMYOPATHY.

## Similar variants {#similar}

Related TRDN variant pages (same residue, condition, or type): [TRDN c.22+1G>T](/variant/trdn-c-22-plus-1g-t), [TRDN c.22+29A>G](/variant/trdn-c-22-plus-29a-g), [TRDN c.391+1G>A](/variant/trdn-c-391-plus-1g-a), [TRDN p.Gln205Ter](/variant/trdn-p-gln205ter), [TRDN p.Glu168Ter](/variant/trdn-p-glu168ter), [TRDN p.Glu181Ter](/variant/trdn-p-glu181ter), [TRDN p.Lys177Ter](/variant/trdn-p-lys177ter), [TRDN p.Met1Thr](/variant/trdn-p-met1thr).

### 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 1900402). 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.*