# NM_000360.4(TH):c.642G>A (p.Arg214=)

https://sugi.bio/variant/th-p-arg214

## Summary

**TH p.Arg214= (c.642G>A)** is classified **Likely benign** in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). Very rare (popmax 0.000255%, nfe); Associated with TH-deficient dopa-responsive dystonia.

**At a glance:** Likely benign · review: Single submitter · rsID rs139579396 · 1 submitter · 1 linked condition · very rare (popmax 0.000255%, nfe)

## For patients & families {#patients}

This is a change in the TH gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Arg214= |
| Coding change (HGVS c.) | c.642G>A |
| MANE Select transcript | [NM_000360](https://www.ncbi.nlm.nih.gov/nuccore/NM_000360) |
| dbSNP | [rs139579396](https://www.ncbi.nlm.nih.gov/snp/rs139579396/) |
| Variant type | single nucleotide variant |
| Location | chr11:2167868-2167868 (GRCh38) |
| ClinVar | [VCV1637165](https://www.ncbi.nlm.nih.gov/clinvar/variation/1637165/) |

**All HGVS expressions:** `NC_000011.10:g.2167868C>T`, `NC_000011.9:g.2189098C>T`, `NG_008128.1:g.8938G>A`, `NM_000360.4:c.642G>A`, `NM_199292.3:c.735G>A`, `NM_199293.3:c.723G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.28) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.181, GERP -1.67, phastCons 0.075 — weakly conserved position
- CADD: **PHRED 12.54**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.09**, acceptor gain **0.00**, donor gain **0.28**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.28**.
- Population frequency (gnomAD v4.1): grpmax **0.000255%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,175,878 in the highest group · 3/1,604,740 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}

**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 Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-19 |

## 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, DYT-TH, TH-deficient dopa-responsive dystonia, Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia, Segawa syndrome, autosomal recessive.

## Same-residue context {#hotspot}

Residue **214** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TH p.Arg214Met](/variant/th-p-arg214met). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TH variant pages (same residue, condition, or type): [TH p.Arg214Met](/variant/th-p-arg214met), [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 2026-10-06); 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 1637165). 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.*