# NM_017775.4(TTC19):c.1030del (p.Ala344fs)

https://sugi.bio/variant/ttc19-p-ala344fs

## Summary

**TTC19 p.Ala344fs (c.1030del)** is classified **Uncertain significance** in TTC19 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-08). Associated with mitochondrial disease.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the TTC19 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to mitochondrial disease.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 104 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027984/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TTC19](https://sugi.bio/atlas/gene/TTC19/) |
| Protein change (HGVS p.) | p.Ala344fs |
| Coding change (HGVS c.) | c.1030del |
| MANE Select transcript | [NM_017775](https://www.ncbi.nlm.nih.gov/nuccore/NM_017775) |
| Variant type | Deletion |
| Location | chr17:16027409-16027409 (GRCh38) |
| ClinVar | [VCV3780758](https://www.ncbi.nlm.nih.gov/clinvar/variation/3780758/) |

**All HGVS expressions:** `NC_000017.10:g.15930723del`, `NC_000017.11:g.16027409del`, `NG_029806.1:g.33030del`, `NG_029806.2:g.32587del`, `NM_001271420.2:c.709del`, `NM_017775.4:c.1030del`

## 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 3.509, GERP 1.9, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.049, pLI 1.5422e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (10 of 10)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**TTC19** population constraint: LOEUF 1.049, pLI 1.5422e-09, missense-Z -0.48028. *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):

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

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.28, 73% of residues very-high.

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

*Describes the biological roles of TTC19 (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}

TTC19 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Complex III assembly](https://reactome.org/content/detail/R-HSA-9865881) | curated |

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

**Biological process:** mitochondrial respiratory chain complex III assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-12-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2021-12-08 |

## Associated conditions {#conditions}

[mitochondrial disease](https://sugi.bio/atlas/disease/mitochondrial-disease/).

**Reported phenotype names (ClinVar):** Mitochondrial disease, Mitochondrial disorders, Mitochondrial disorder.

## Similar variants {#similar}

Related TTC19 variant pages (same residue, condition, or type): [TTC19 p.Gln151Ter](/variant/ttc19-p-gln151ter), [TTC19 p.Gly201fs](/variant/ttc19-p-gly201fs), [TTC19 c.832-13_832-10del](/variant/ttc19-c-832-minus-13-832-minus-10del), [TTC19 p.Lys369_Lys370insTer](/variant/ttc19-p-lys369-lys370inster), [TTC19 c.581+1_581+5del](/variant/ttc19-c-581-plus-1-581-plus-5del), [TTC19 c.677-1_680del](/variant/ttc19-c-677-minus-1-680del), [TTC19 p.Glu156fs](/variant/ttc19-p-glu156fs), [TTC19 c.312+3_312+76del](/variant/ttc19-c-312-plus-3-312-plus-76del).

### 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 3780758). 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.*