# NM_017775.4(TTC19):c.997C>T (p.Arg333Ter)

https://sugi.bio/variant/ttc19-p-arg333ter

## Summary

**TTC19 p.Arg333Ter (c.997C>T)** is classified **Conflicting classifications of pathogenicity** in TTC19 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-25). Very rare (popmax 0.00267%, afr); Associated with mitochondrial complex III deficiency nuclear type 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs192522753 · 3 submitters · 1 linked condition · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the TTC19 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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.Arg333Ter |
| Coding change (HGVS c.) | c.997C>T |
| MANE Select transcript | [NM_017775](https://www.ncbi.nlm.nih.gov/nuccore/NM_017775) |
| dbSNP | [rs192522753](https://www.ncbi.nlm.nih.gov/snp/rs192522753/) |
| Variant type | single nucleotide variant |
| Location | chr17:16027376-16027376 (GRCh38) |
| ClinVar | [VCV215305](https://www.ncbi.nlm.nih.gov/clinvar/variation/215305/) |

**All HGVS expressions:** `NC_000017.10:g.15930690C>T`, `NC_000017.11:g.16027376C>T`, `NG_029806.1:g.32997C>T`, `NM_001271420.2:c.676C>T`, `NM_017775.4:c.997C>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 2.872, GERP 0.973, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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.
- CADD: **PHRED 39.0**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.45 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.*
- Pangolin: Δ**0.39** (loss), gain 0.00 / loss 0.39. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.00145% · FAF99 0.00123% · 2/74,946 in the highest group · 37/1,613,748 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0109% | 9,144 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,251 |
| African / African-American (grpmax) | 0.00267% | 37,473 |
| European (non-Finnish) | 0.00212% | 47,192 |
| Admixed American | 0.00167% | 59,992 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-08-25.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 3 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-03-03 |
| Neuberg Centre For Genomic Medicine, NCGM | Uncertain significance | criteria provided, single submitter | clinical testing |  |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-25 |

## 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 p.Arg333Gln](/variant/ttc19-p-arg333gln), [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), [TTC19 p.Ala263Ser](/variant/ttc19-p-ala263ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 215305). 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.*