# NM_006996.3(SLC19A2):c.1380C>T (p.Ala460=)

https://sugi.bio/variant/slc19a2-p-ala460

## Summary

**SLC19A2 p.Ala460= (c.1380C>T)** is classified **Likely benign** in SLC19A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-22). Ultra-rare (popmax 0.04%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs151078749 · 1 submitter · ultra-rare (popmax 0.04%, afr)

## For patients & families {#patients}

This is a change in the SLC19A2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [SLC19A2](https://sugi.bio/atlas/gene/SLC19A2/) |
| Protein change (HGVS p.) | p.Ala460= |
| Coding change (HGVS c.) | c.1380C>T |
| MANE Select transcript | [NM_006996](https://www.ncbi.nlm.nih.gov/nuccore/NM_006996) |
| dbSNP | [rs151078749](https://www.ncbi.nlm.nih.gov/snp/rs151078749/) |
| Variant type | single nucleotide variant |
| Location | chr1:169465963-169465963 (GRCh38) |
| ClinVar | [VCV724315](https://www.ncbi.nlm.nih.gov/clinvar/variation/724315/) |

**All HGVS expressions:** `NC_000001.10:g.169435201G>A`, `NC_000001.11:g.169465963G>A`, `NG_008255.1:g.25008C>T`, `NM_001319667.1:c.777C>T`, `NM_006996.3:c.1380C>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 loss** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.779, GERP -3.96 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.133**. 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 **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.23**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.40** (loss), gain 0.00 / loss 0.40. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.04%** (afr) · FAF95 0.0288% · FAF99 0.0249% · 30/74,974 in the highest group · 36/1,613,862 alleles overall — ultra-rare (popmax 0.04%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.04% | 2,499 |
| Admixed American | 0.00333% | 29,995 |
| South Asian | 0.0022% | 45,531 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,496 |
| European (non-Finnish) | 8.48e-05% | 1,179,917 |

*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}

**SLC19A2** population constraint: LOEUF 0.852, pLI 2.0312e-06, missense-Z 0.8925. *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 **460** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.99, 54% of residues very-high.

**2 experimental structure(s)** (PDB): [8Z7Z](https://www.rcsb.org/structure/8Z7Z), [8Z80](https://www.rcsb.org/structure/8Z80).

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

*Describes the biological roles of SLC19A2 (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:** SLC19A2's established molecular role includes thiamine transmembrane transporter activity.


### Pathways affected {#pathways}

SLC19A2 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}

**Molecular function:** thiamine transmembrane transporter activity.

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

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-22.

**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 | 2026-01-22 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related SLC19A2 variant pages (same residue, condition, or type): [SLC19A2 c.1223+1G>A](/variant/slc19a2-c-1223-plus-1g-a), [SLC19A2 c.807+2T>G](/variant/slc19a2-c-807-plus-2t-g), [SLC19A2 p.Arg162Ter](/variant/slc19a2-p-arg162ter), [SLC19A2 p.Arg397Ter](/variant/slc19a2-p-arg397ter), [SLC19A2 p.Gln233Ter](/variant/slc19a2-p-gln233ter), [SLC19A2 p.Glu66Ter](/variant/slc19a2-p-glu66ter), [SLC19A2 p.Gly105Glu](/variant/slc19a2-p-gly105glu), [SLC19A2 p.Gly172Asp](/variant/slc19a2-p-gly172asp).

### 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 724315). 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.*