# NM_025243.4(SLC19A3):c.125dup (p.Asp43fs)

https://sugi.bio/variant/slc19a3-p-asp43fs

## Summary

**SLC19A3 p.Asp43fs (c.125dup)** is classified **Pathogenic** in SLC19A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). Very rare (popmax 6.2e-05%); Associated with biotin-responsive basal ganglia disease.

**At a glance:** Pathogenic · review: Single submitter · rsID rs866002450 · 1 submitter · 1 linked condition · very rare (popmax 6.2e-05%)

## For patients & families {#patients}

This is a change in the SLC19A3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to biotin-responsive basal ganglia disease.

*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 |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SLC19A3 is a diagnostic-grade gene on 16 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010237/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SLC19A3](https://sugi.bio/atlas/gene/SLC19A3/) |
| Protein change (HGVS p.) | p.Asp43fs |
| Coding change (HGVS c.) | c.125dup |
| MANE Select transcript | [NM_025243](https://www.ncbi.nlm.nih.gov/nuccore/NM_025243) |
| dbSNP | [rs866002450](https://www.ncbi.nlm.nih.gov/snp/rs866002450/) |
| Variant type | Duplication |
| Location | chr2:227702193-227702194 (GRCh38) |
| ClinVar | [VCV2762268](https://www.ncbi.nlm.nih.gov/clinvar/variation/2762268/) |

**All HGVS expressions:** `NC_000002.11:g.228566911dup`, `NC_000002.12:g.227702195dup`, `NG_016359.1:g.20836dup`, `NM_001371411.1:c.125dup`, `NM_001371412.1:c.125dup`, `NM_001371413.1:c.-84dup`, `NM_001371414.1:c.-84dup`, `NM_025243.4:c.125dup`

## 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 0.044, GERP -3.75, phastCons 0.004 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.968, pLI 1.2033e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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): global (via dbSNP) **6.2e-05%** · 1/1,613,954 alleles overall — very rare (popmax 6.2e-05%).

*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}

**SLC19A3** population constraint: LOEUF 0.968, pLI 1.2033e-07, missense-Z 0.51867. *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):

- **Leigh syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **43** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 81.96, 55% of residues very-high.

**19 experimental structure(s)** (PDB): [8S4U](https://www.rcsb.org/structure/8S4U), [8S5U](https://www.rcsb.org/structure/8S5U), [8S5W](https://www.rcsb.org/structure/8S5W), [8S5Z](https://www.rcsb.org/structure/8S5Z), [8S61](https://www.rcsb.org/structure/8S61), [8S62](https://www.rcsb.org/structure/8S62).

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

*Describes the biological roles of SLC19A3 (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}

SLC19A3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Vitamin B1 (thiamin) metabolism](https://reactome.org/content/detail/R-HSA-196819) | curated |

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

**Biological process:** thiamine transport, pyridoxine transport.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-05.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-05 |

## Associated conditions {#conditions}

[biotin-responsive basal ganglia disease](https://sugi.bio/atlas/disease/biotin-responsive-basal-ganglia-disease/).

**Reported phenotype names (ClinVar):** Biotin-responsive basal ganglia disease, Thiamine metabolism dysfunction syndrome type 2, THIAMINE METABOLISM DYSFUNCTION SYNDROME 2 (BIOTIN- AND THIAMINE-RESPONSIVE TYPE), Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2), thiamine-responsive encephalopathy, Thiamine Transporter-2 Deficiency.

## Similar variants {#similar}

Related SLC19A3 variant pages (same residue, condition, or type): [SLC19A3 p.Asp43Asn](/variant/slc19a3-p-asp43asn), [SLC19A3 p.Leu360fs](/variant/slc19a3-p-leu360fs), [SLC19A3 p.Met28fs](/variant/slc19a3-p-met28fs), [SLC19A3 p.Ser26fs](/variant/slc19a3-p-ser26fs), [SLC19A3 p.Val103fs](/variant/slc19a3-p-val103fs), [SLC19A3 p.Asn297fs](/variant/slc19a3-p-asn297fs), [SLC19A3 p.Lys44Ter](/variant/slc19a3-p-lys44ter), [SLC19A3 p.Tyr462Ter](/variant/slc19a3-p-tyr462ter).

### 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 2762268). 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.*