# NM_017775.4(TTC19):c.601_604del (p.Gly201fs)

https://sugi.bio/variant/ttc19-p-gly201fs

## Summary

**TTC19 p.Gly201fs (c.601_604del)** is classified **Pathogenic** in TTC19 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-12). Very rare (popmax 0.000255%, nfe); Associated with mitochondrial complex III deficiency nuclear type 2.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs794726691 · 6 submitters · 1 linked condition · very rare (popmax 0.000255%, nfe)

## For patients & families {#patients}

This is a change in the TTC19 gene that is considered disease-causing, submitted by 6 submitters, and is linked to mitochondrial complex III deficiency nuclear type 2.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015910/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.Gly201fs |
| Coding change (HGVS c.) | c.601_604del |
| MANE Select transcript | [NM_017775](https://www.ncbi.nlm.nih.gov/nuccore/NM_017775) |
| dbSNP | [rs794726691](https://www.ncbi.nlm.nih.gov/snp/rs794726691/) |
| Variant type | Deletion |
| Location | chr17:16006490-16006493 (GRCh38) |
| ClinVar | [VCV102437](https://www.ncbi.nlm.nih.gov/clinvar/variation/102437/) |

**All HGVS expressions:** `NC_000017.10:g.15909807_15909810del`, `NC_000017.11:g.16006493_16006496del`, `NG_029806.1:g.12114_12117del`, `NM_001271420.2:c.280_283del`, `NM_017775.3:c.601_604del`, `NM_017775.4:c.601_604del`

## 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 0.858, GERP 0.573, phastCons 1 — weakly conserved position
- 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 exon 7 of 10**, so the transcript is predicted to undergo NMD.
- 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.
- Population frequency (gnomAD v4.1): grpmax **0.000255%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,178,632 in the highest group · 3/1,612,378 alleles overall — very rare (popmax 0.000255%, nfe).

*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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-12.

**Submitter consensus:** unanimous (6/6 Pathogenic).

**Submission history:** 6 submissions (2013–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-05-01 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-30 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-02 |
| Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-19 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-12 |

## Associated conditions {#conditions}

[mitochondrial complex III deficiency nuclear type 2](https://sugi.bio/atlas/disease/mitochondrial-complex-iii-deficiency-nuclear-type-2/).

**Reported phenotype names (ClinVar):** Mitochondrial complex III deficiency nuclear type 2, not provided, none provided.

## Similar variants {#similar}

Related TTC19 variant pages (same residue, condition, or type): [TTC19 c.581+1_581+5del](/variant/ttc19-c-581-plus-1-581-plus-5del), [TTC19 p.Glu156fs](/variant/ttc19-p-glu156fs), [TTC19 p.Gln195Ter](/variant/ttc19-p-gln195ter), [TTC19 p.Leu185Pro](/variant/ttc19-p-leu185pro), [TTC19 p.Leu219Ter](/variant/ttc19-p-leu219ter), [TTC19 c.581+4A>C](/variant/ttc19-c-581-plus-4a-c), [TTC19 c.994+3A>T](/variant/ttc19-c-994-plus-3a-t), [TTC19 p.Ala122Thr](/variant/ttc19-p-ala122thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 102437). 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.*