# NM_000353.3(TAT):c.207A>G (p.Pro69=)

https://sugi.bio/variant/tat-p-pro69

## Summary

**TAT p.Pro69= (c.207A>G)** is classified **Likely benign** in TAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). Very rare (popmax 0.000424%, nfe); Associated with tyrosinemia type II.

**At a glance:** Likely benign · review: Single submitter · rsID rs1383405389 · 1 submitter · 1 linked condition · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the TAT gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to tyrosinemia type II.

*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) | Adolescent, Childhood, Infancy, Neonatal |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TAT is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Tyrosinemia type 2** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperkeratosis — Very frequent (99-80%)
- Palmoplantar keratoderma — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Corneal opacity — Very frequent (99-80%)
- Photophobia — Frequent (79-30%)
- Nystagmus — Frequent (79-30%)
- Atypical behavior — Frequent (79-30%)
- Hyperhidrosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003105/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TAT](https://sugi.bio/atlas/gene/TAT/) |
| Protein change (HGVS p.) | p.Pro69= |
| Coding change (HGVS c.) | c.207A>G |
| MANE Select transcript | [NM_000353](https://www.ncbi.nlm.nih.gov/nuccore/NM_000353) |
| dbSNP | [rs1383405389](https://www.ncbi.nlm.nih.gov/snp/rs1383405389/) |
| Variant type | single nucleotide variant |
| Location | chr16:71576209-71576209 (GRCh38) |
| ClinVar | [VCV1112520](https://www.ncbi.nlm.nih.gov/clinvar/variation/1112520/) |

**All HGVS expressions:** `NC_000016.10:g.71576209T>C`, `NC_000016.9:g.71610112T>C`, `NG_008235.1:g.5887A>G`, `NM_000353.3:c.207A>G`

## 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 -1.666, GERP -3.81 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.889**. 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 (T>A, 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 **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,180,024 in the highest group · 5/1,461,848 alleles overall — very rare (popmax 0.000424%, 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}

**TAT** population constraint: LOEUF 0.844, pLI 9.3349e-08, missense-Z 1.0469. *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):

- **tyrosinemia type II** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.93, 86% of residues very-high.

**1 experimental structure(s)** (PDB): [3DYD](https://www.rcsb.org/structure/3DYD).

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

*Describes the biological roles of TAT (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:** TAT's established molecular role includes L-tyrosine:2-oxoglutarate transaminase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Tyrosine catabolism](https://reactome.org/content/detail/R-HSA-8963684) | curated |

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

**Molecular function:** L-tyrosine:2-oxoglutarate transaminase activity, identical protein binding.

**Biological process:** 2-oxoglutarate metabolic process, glutamate metabolic process, L-tyrosine catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-30.

**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 | 2024-01-30 |

## Associated conditions {#conditions}

[tyrosinemia type II](https://sugi.bio/atlas/disease/tyrosinemia-type-ii/).

**Reported phenotype names (ClinVar):** Tyrosinemia type II, KERATOSIS PALMOPLANTARIS WITH CORNEAL DYSTROPHY, OREGON TYPE TYROSINEMIA, TAT DEFICIENCY, TYROSINE AMINOTRANSFERASE DEFICIENCY, TYROSINE TRANSAMINASE DEFICIENCY.

## Similar variants {#similar}

Related TAT variant pages (same residue, condition, or type): [TAT p.Pro69Ser](/variant/tat-p-pro69ser), [TAT c.707-2A>G](/variant/tat-c-707-minus-2a-g), [TAT c.912+1G>A](/variant/tat-c-912-plus-1g-a), [TAT p.Arg119Trp](/variant/tat-p-arg119trp), [TAT p.Arg297Ter](/variant/tat-p-arg297ter), [TAT p.Arg306Ter](/variant/tat-p-arg306ter), [TAT p.Arg417Gln](/variant/tat-p-arg417gln), [TAT p.Arg417Ter](/variant/tat-p-arg417ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1112520). 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.*