# NM_006996.3(SLC19A2):c.203A>T (p.Glu68Val)

https://sugi.bio/variant/slc19a2-p-glu68val

## Summary

**SLC19A2 p.Glu68Val (c.203A>T)** is classified **Uncertain significance** in SLC19A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely benign (0.324); Very rare (popmax 0.000257%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000257%, nfe)

## For patients & families {#patients}

This is a change in the SLC19A2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.Glu68Val |
| Coding change (HGVS c.) | c.203A>T |
| MANE Select transcript | [NM_006996](https://www.ncbi.nlm.nih.gov/nuccore/NM_006996) |
| Variant type | single nucleotide variant |
| Location | chr1:169485564-169485564 (GRCh38) |
| ClinVar | [VCV4631050](https://www.ncbi.nlm.nih.gov/clinvar/variation/4631050/) |

**All HGVS expressions:** `NC_000001.10:g.169454802T>A`, `NC_000001.11:g.169485564T>A`, `NG_008255.1:g.5407A>T`, `NG_164937.1:g.76T>A`, `NM_001319667.1:c.203A>T`, `NM_006996.3:c.203A>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.324)
- REVEL 0.52 (indeterminate)
- SaProt LLR -7.649 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.34) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.656, GERP 2.08, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.0**. 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.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (169,465,852–169,485,766), spanning 19,914 bp. Chi-square p 0.054. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.09**, acceptor gain **0.00**, donor gain **0.34**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.34**.
- Pangolin: Δ**0.23** (gain), gain 0.23 / loss 0.20. 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 **0.000257%** (nfe) · FAF95 6.9e-05% · FAF99 1.9e-05% · 3/1,165,422 in the highest group · 3/1,583,600 alleles overall — very rare (popmax 0.000257%, 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}

**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}


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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-06.

**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 | 2025-10-06 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related SLC19A2 variant pages (same residue, condition, or type): [SLC19A2 p.Ala201Gly](/variant/slc19a2-p-ala201gly), [SLC19A2 p.Ala431Ser](/variant/slc19a2-p-ala431ser), [SLC19A2 p.Arg275Cys](/variant/slc19a2-p-arg275cys), [SLC19A2 p.Glu321Lys](/variant/slc19a2-p-glu321lys), [SLC19A2 p.Gly184Ser](/variant/slc19a2-p-gly184ser), [SLC19A2 p.Gly235Ser](/variant/slc19a2-p-gly235ser), [SLC19A2 p.Gly362Glu](/variant/slc19a2-p-gly362glu), [SLC19A2 p.Gly447Ser](/variant/slc19a2-p-gly447ser).

### 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 4631050). 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.*