# NM_000360.4(TH):c.628G>T (p.Ala210Ser)

https://sugi.bio/variant/th-p-ala210ser

## Summary

**TH p.Ala210Ser (c.628G>T)** is classified **Uncertain significance** in TH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-23). AlphaMissense: likely benign (0.3065); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1260455415 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0165%, mid)

## 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 2 submitters, and is linked to Inborn genetic diseases.

*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 | [TH](https://sugi.bio/atlas/gene/TH/) |
| Protein change (HGVS p.) | p.Ala210Ser |
| Coding change (HGVS c.) | c.628G>T |
| MANE Select transcript | [NM_000360](https://www.ncbi.nlm.nih.gov/nuccore/NM_000360) |
| dbSNP | [rs1260455415](https://www.ncbi.nlm.nih.gov/snp/rs1260455415/) |
| Variant type | single nucleotide variant |
| Location | chr11:2167882-2167882 (GRCh38) |
| ClinVar | [VCV1437804](https://www.ncbi.nlm.nih.gov/clinvar/variation/1437804/) |

**All HGVS expressions:** `NC_000011.10:g.2167882C>A`, `NC_000011.9:g.2189112C>A`, `NG_008128.1:g.8924G>T`, `NM_000360.4:c.628G>T`, `NM_199292.2:c.721G>T`, `NM_199292.3:c.721G>T`, `NM_199293.3:c.709G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3065)
- REVEL 0.899 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -9.345 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 5.687, GERP 1.24, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A241S** vs ClinVar **A210S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 26.8**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.30 donor loss), 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 **0.0165%** (mid) · 1/6,052 in the highest group · 1/1,608,190 alleles overall — ultra-rare (popmax 0.0165%, mid).

*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}

Residue **241** lies in a UniProt-annotated variant site (in arsegs; loss of over 80% of tyrosine 3-monooxygenase activity); an α-helix.

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 2023-06-23.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-18 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-23 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [TH-deficient dopa-responsive dystonia](https://sugi.bio/atlas/disease/th-deficient-dopa-responsive-dystonia/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Autosomal recessive DOPA responsive dystonia, DYT-TH, TH-deficient dopa-responsive dystonia, Segawa syndrome, autosomal recessive, Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia.

## Same-residue context {#hotspot}

Residue **210** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TH p.Ala210Thr](/variant/th-p-ala210thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TH variant pages (same residue, condition, or type): [TH p.Ala210Thr](/variant/th-p-ala210thr), [TH p.Ala210=](/variant/th-p-ala210), [TH p.Ala210Gly](/variant/th-p-ala210gly), [TH p.Ala210Val](/variant/th-p-ala210val), [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).

### 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 1437804). 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.*