# NM_000360.4(TH):c.594G>T (p.Val198=)

https://sugi.bio/variant/th-p-val198

## Summary

**TH p.Val198= (c.594G>T)** is classified **Likely benign** in TH (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Rare (popmax 0.116%, mid); Associated with TH-deficient dopa-responsive dystonia.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs544661832 · 7 submitters · 1 linked condition · rare (popmax 0.116%, mid)

## For patients & families {#patients}

This is a change in the TH gene that is classified as likely benign — not considered disease-causing, submitted by 7 submitters, and is linked to TH-deficient dopa-responsive dystonia.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | TH is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Autosomal recessive dopa-responsive dystonia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Ptosis — Frequent (79-30%)
- Irritability — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Ataxia — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)
- Lethargy — Frequent (79-30%)
- Motor delay — Frequent (79-30%)
- Parkinsonism — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001902/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TH](https://sugi.bio/atlas/gene/TH/) |
| Protein change (HGVS p.) | p.Val198= |
| Coding change (HGVS c.) | c.594G>T |
| MANE Select transcript | [NM_000360](https://www.ncbi.nlm.nih.gov/nuccore/NM_000360) |
| dbSNP | [rs544661832](https://www.ncbi.nlm.nih.gov/snp/rs544661832/) |
| Variant type | single nucleotide variant |
| Location | chr11:2167916-2167916 (GRCh38) |
| ClinVar | [VCV696505](https://www.ncbi.nlm.nih.gov/clinvar/variation/696505/) |

**All HGVS expressions:** `NC_000011.10:g.2167916C>A`, `NC_000011.9:g.2189146C>A`, `NG_008128.1:g.8890G>T`, `NM_000360.4:c.594G>T`, `NM_199292.3:c.687G>T`, `NM_199293.3:c.675G>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 -3.644, GERP 0.007 — fast-evolving / accelerated position
- CADD: **PHRED 4.098**. 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>T, Δ0.20 donor 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 **0.116%** (mid) · FAF95 0.0542% · FAF99 0.0384% · 7/6,058 in the highest group · 256/1,611,532 alleles overall — rare (popmax 0.116%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.254% | 394 |
| Middle Eastern (grpmax) | 0.116% | 865 |
| Admixed American | 0.0534% | 1,872 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,120 |
| South Asian | 0.0165% | 6,052 |
| European (non-Finnish) | 0.00882% | 11,340 |
| African / African-American | 0.004% | 25,003 |

Ashkenazi Jewish 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}

**TH** population constraint: LOEUF 1.27, pLI 3.3283e-17, missense-Z -1.0314. *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):

- **tyrosine hydroxylase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.75, 59% of residues very-high.

**7 experimental structure(s)** (PDB): [2XSN](https://www.rcsb.org/structure/2XSN), [4J6S](https://www.rcsb.org/structure/4J6S), [6ZN2](https://www.rcsb.org/structure/6ZN2), [6ZVP](https://www.rcsb.org/structure/6ZVP), [6ZZU](https://www.rcsb.org/structure/6ZZU), [7A2G](https://www.rcsb.org/structure/7A2G).

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

*Describes the biological roles of TH (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.*

**How this variant is thought to act:** TH's established molecular role includes tyrosine 3-monooxygenase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Catecholamine biosynthesis](https://reactome.org/content/detail/R-HSA-209905) | curated |

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

**Molecular function:** tyrosine 3-monooxygenase activity, enzyme binding, identical protein binding.

**Biological process:** response to hypoxia, dopamine biosynthetic process, epinephrine biosynthetic process, norepinephrine biosynthetic process, response to ethanol.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-28.

**Submitter consensus:** conflicting (6 Likely benign, 1 Uncertain significance).

**Submission history:** 7 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-24 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-11-01 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-12 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-23 |

## Associated conditions {#conditions}

[TH-deficient dopa-responsive dystonia](https://sugi.bio/atlas/disease/th-deficient-dopa-responsive-dystonia/).

**Reported phenotype names (ClinVar):** Autosomal recessive DOPA responsive dystonia, not provided, TH-related disorder, not specified, Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia, DYT-TH, TH-deficient dopa-responsive dystonia, Segawa syndrome, autosomal recessive, TH-related condition, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **198** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TH p.Val198fs](/variant/th-p-val198fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TH variant pages (same residue, condition, or type): [TH p.Val198fs](/variant/th-p-val198fs), [TH c.1200+2T>C](/variant/th-c-1200-plus-2t-c), [TH c.1334+1G>A](/variant/th-c-1334-plus-1g-a), [TH c.312+1G>A](/variant/th-c-312-plus-1g-a), [TH c.488-1G>A](/variant/th-c-488-minus-1g-a), [TH c.644+1G>A](/variant/th-c-644-plus-1g-a), [TH c.695+1G>C](/variant/th-c-695-plus-1g-c), [TH c.90+10C>T](/variant/th-c-90-plus-10c-t).

### 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 696505). 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.*