# NM_000452.3(SLC10A2):c.556del (p.Trp186fs)

https://sugi.bio/variant/slc10a2-p-trp186fs

## Summary

**SLC10A2 p.Trp186fs (c.556del)** is classified **Conflicting classifications of pathogenicity** in SLC10A2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-29). Rare (popmax 0.132%, sas); Associated with bile acid malabsorption, primary, 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs781456338 · 3 submitters · 1 linked condition · rare (popmax 0.132%, sas)

## For patients & families {#patients}

This is a change in the SLC10A2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to bile acid malabsorption, primary, 1.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | SLC10A2 is a diagnostic-grade gene on 1 Genomics England panel |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SLC10A2](https://sugi.bio/atlas/gene/SLC10A2/) |
| Protein change (HGVS p.) | p.Trp186fs |
| Coding change (HGVS c.) | c.556del |
| MANE Select transcript | [NM_000452](https://www.ncbi.nlm.nih.gov/nuccore/NM_000452) |
| dbSNP | [rs781456338](https://www.ncbi.nlm.nih.gov/snp/rs781456338/) |
| Variant type | Deletion |
| Location | chr13:103052649-103052649 (GRCh38) |
| ClinVar | [VCV2868591](https://www.ncbi.nlm.nih.gov/clinvar/variation/2868591/) |

**All HGVS expressions:** `NC_000013.10:g.103704999del`, `NC_000013.11:g.103052649del`, `NG_016648.1:g.19198del`, `NM_000452.3:c.556del`, `NM_000452.3:c.556delT`

## 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 7.617, GERP 1.6, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.464, pLI 5.8838e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 6**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.132%** (sas) · FAF95 0.113% · FAF99 0.105% · 120/91,038 in the highest group · 158/1,611,426 alleles overall — rare (popmax 0.132%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.132% | 759 |
| Middle Eastern | 0.0988% | 1,012 |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,199 |
| European (non-Finnish) | 0.0017% | 58,891 |

*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}

**SLC10A2** population constraint: LOEUF 1.464, pLI 5.8838e-10, missense-Z -1.0034. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.88, 51% of residues very-high.

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

*Describes the biological roles of SLC10A2 (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}

SLC10A2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Recycling of bile acids and salts](https://reactome.org/content/detail/R-HSA-159418) | curated |

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-29.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Pathogenic).

**Submission history:** 3 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-29 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-11 |

## Associated conditions {#conditions}

[bile acid malabsorption, primary, 1](https://sugi.bio/atlas/disease/bile-acid-malabsorption-primary-1/).

**Reported phenotype names (ClinVar):** Bile acid malabsorption, primary, 1, not provided, none provided, Bile acid malabsorption, primary.

## Similar variants {#similar}

Related SLC10A2 variant pages (same residue, condition, or type): [SLC10A2 p.Trp186Ter](/variant/slc10a2-p-trp186ter), [SLC10A2 p.Ala116Val](/variant/slc10a2-p-ala116val), [SLC10A2 p.Arg256Ter](/variant/slc10a2-p-arg256ter), [SLC10A2 p.Cys105Arg](/variant/slc10a2-p-cys105arg), [SLC10A2 p.Cys144Tyr](/variant/slc10a2-p-cys144tyr), [SLC10A2 p.Gly77Glu](/variant/slc10a2-p-gly77glu), [SLC10A2 p.Pro251Leu](/variant/slc10a2-p-pro251leu), [SLC10A2 p.Ser133Cys](/variant/slc10a2-p-ser133cys).

### 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 2026-07-14); 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 2868591). 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.*