# NM_006440.5(TXNRD2):c.1458C>T (p.Ser486=)

https://sugi.bio/variant/txnrd2-p-ser486

## Summary

**TXNRD2 p.Ser486= (c.1458C>T)** is classified **Uncertain significance** in TXNRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-05). Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the TXNRD2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Cardiovascular phenotype.

*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 | [TXNRD2](https://sugi.bio/atlas/gene/TXNRD2/) |
| Protein change (HGVS p.) | p.Ser486= |
| Coding change (HGVS c.) | c.1458C>T |
| MANE Select transcript | [NM_006440](https://www.ncbi.nlm.nih.gov/nuccore/NM_006440) |
| Variant type | single nucleotide variant |
| Location | chr22:19877222-19877222 (GRCh38) |
| ClinVar | [VCV3976399](https://www.ncbi.nlm.nih.gov/clinvar/variation/3976399/) |

**All HGVS expressions:** `LRG_417:g.69615C>T`, `LRG_417t1:c.1458C>T`, `NC_000022.10:g.19864745G>A`, `NC_000022.11:g.19877222G>A`, `NG_011835.1:g.69615C>T`, `NM_001352300.2:c.1455C>T`, `NM_001352301.2:c.1368C>T`, `NM_001352302.2:c.1170C>T`, `NM_006440.5:c.1458C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.38) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.021, GERP -2.18, phastCons 0.664 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.68**. 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 **0.01**, donor loss **0.00**, acceptor gain **0.38**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.38**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,946 in the highest group · 1/1,610,970 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**TXNRD2** population constraint: LOEUF 1.18, pLI 2.0999e-22, missense-Z 0.74275. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **486** lies in a UniProt-annotated variant site (in gccd5; the mutant protein is undetectable in patient cells).

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

*Describes the biological roles of TXNRD2 (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.*


### Pathways affected {#pathways}

TXNRD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Detoxification of Reactive Oxygen Species](https://reactome.org/content/detail/R-HSA-3299685) | other |

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

**Biological process:** cell redox homeostasis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-05 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Similar variants {#similar}

Related TXNRD2 variant pages (same residue, condition, or type): [TXNRD2 c.104-3C>G](/variant/txnrd2-c-104-minus-3c-g), [TXNRD2 c.1182+5G>A](/variant/txnrd2-c-1182-plus-5g-a), [TXNRD2 c.172+3A>G](/variant/txnrd2-c-172-plus-3a-g), [TXNRD2 c.450-1G>A](/variant/txnrd2-c-450-minus-1g-a), [TXNRD2 c.528+2T>C](/variant/txnrd2-c-528-plus-2t-c), [TXNRD2 c.591+1G>A](/variant/txnrd2-c-591-plus-1g-a), [TXNRD2 c.662+1G>A](/variant/txnrd2-c-662-plus-1g-a), [TXNRD2 p.Ala131Gly](/variant/txnrd2-p-ala131gly).

### 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 3976399). 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.*