# NM_017775.4(TTC19):c.752A>G (p.Lys251Arg)

https://sugi.bio/variant/ttc19-p-lys251arg

## Summary

**TTC19 p.Lys251Arg (c.752A>G)** is classified **Uncertain significance** in TTC19 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-02). AlphaMissense: likely benign (0.0738); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## 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.

*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 | [TTC19](https://sugi.bio/atlas/gene/TTC19/) |
| Protein change (HGVS p.) | p.Lys251Arg |
| Coding change (HGVS c.) | c.752A>G |
| MANE Select transcript | [NM_017775](https://www.ncbi.nlm.nih.gov/nuccore/NM_017775) |
| Variant type | single nucleotide variant |
| Location | chr17:16025092-16025092 (GRCh38) |
| ClinVar | [VCV3663420](https://www.ncbi.nlm.nih.gov/clinvar/variation/3663420/) |

**All HGVS expressions:** `NC_000017.10:g.15928406A>G`, `NC_000017.11:g.16025092A>G`, `NG_029806.1:g.30713A>G`, `NG_029806.2:g.30270A>G`, `NM_001271420.2:c.431A>G`, `NM_017775.4:c.752A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0738)
- REVEL 0.405 (indeterminate)
- SaProt LLR -5.684 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- SpliceAI predicts **acceptor gain** (Δ 0.69) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.017, GERP 1.9, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.4**. 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 0.99** across the covering region of the MANE Select transcript (15,999,849–16,027,519), spanning 27,670 bp. Chi-square p 0.9. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.69**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.69**, donor gain **0.00**.
- Pangolin: Δ**0.39** (gain), gain 0.39 / loss 0.00. Agrees with SpliceAI. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 2024-11-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-02 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related TTC19 variant pages (same residue, condition, or type): [TTC19 c.581+1G>C](/variant/ttc19-c-581-plus-1g-c), [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.Ala200Val](/variant/ttc19-p-ala200val).

### 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 3663420). 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.*