# NM_000360.4(TH):c.406G>A (p.Val136Met)

https://sugi.bio/variant/th-p-val136met

## Summary

**TH p.Val136Met (c.406G>A)** is classified **Uncertain significance** in TH (ClinVar, Multiple submitters, 8 submitters; last evaluated 2023-08-03). AlphaMissense: likely benign (0.3251); Ultra-rare (popmax 0.0262%, nfe); Associated with TH-deficient dopa-responsive dystonia.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs142046543 · 8 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0262%, nfe)

## For patients & families {#patients}

This is a change in the TH gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 8 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.Val136Met |
| Coding change (HGVS c.) | c.406G>A |
| MANE Select transcript | [NM_000360](https://www.ncbi.nlm.nih.gov/nuccore/NM_000360) |
| dbSNP | [rs142046543](https://www.ncbi.nlm.nih.gov/snp/rs142046543/) |
| Variant type | single nucleotide variant |
| Location | chr11:2168572-2168572 (GRCh38) |
| ClinVar | [VCV304078](https://www.ncbi.nlm.nih.gov/clinvar/variation/304078/) |

**All HGVS expressions:** `NC_000011.10:g.2168572C>T`, `NC_000011.9:g.2189802C>T`, `NG_008128.1:g.8234G>A`, `NM_000360.4:c.406G>A`, `NM_199292.3:c.499G>A`, `NM_199293.3:c.487G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.3251)
- REVEL 0.491 (indeterminate)
- SaProt LLR -11.826 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.648, GERP -0.426, phastCons 1 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **V167M** vs ClinVar **V136M**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 18.82**. 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 1.03** across the covering region of the MANE Select transcript (2,164,236–2,171,786), spanning 7,550 bp. Chi-square p 0.38. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.26**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.02**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0262%** (nfe) · FAF95 0.0238% · FAF99 0.0229% · 309/1,179,678 in the highest group · 330/1,611,688 alleles overall — ultra-rare (popmax 0.0262%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0262% | 3,818 |
| Remaining individuals (not grpmax-eligible) | 0.0241% | 4,155 |
| African / African-American | 0.00534% | 18,724 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,566 |
| Admixed American | 0.00167% | 59,954 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-08-03.

**Submitter consensus:** unanimous (8/8 Uncertain significance).

**Submission history:** 8 submissions (2018–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-24 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-03 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-09-16 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-01-08 |

## 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, none provided, Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia, DYT-TH, TH-deficient dopa-responsive dystonia, Segawa syndrome, autosomal recessive.

## Same-residue context {#hotspot}

Residue **136** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TH p.Val136Glu](/variant/th-p-val136glu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TH variant pages (same residue, condition, or type): [TH p.Val136Glu](/variant/th-p-val136glu), [TH p.Val136=](/variant/th-p-val136), [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).

### 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 304078). 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.*