# NM_006996.3(SLC19A2):c.759dup (p.Glu254Ter)

https://sugi.bio/variant/slc19a2-p-glu254ter

## Summary

**SLC19A2 p.Glu254Ter (c.759dup)** is classified **Pathogenic** in SLC19A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-18). Very rare (popmax 0.005%, amr); Associated with thiamine-responsive megaloblastic anemia syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1368720035 · 2 submitters · 1 linked condition · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the SLC19A2 gene that is considered disease-causing, submitted by 2 submitters, and is linked to thiamine-responsive megaloblastic anemia syndrome.

*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) | Childhood |
| Diagnostic panels | SLC19A2 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Thiamine-responsive megaloblastic anemia syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Diabetes mellitus — Very frequent (99-80%)
- Pallor — Very frequent (99-80%)
- Lethargy — Very frequent (99-80%)
- Megaloblastic anemia — Very frequent (99-80%)
- Diarrhea — Very frequent (99-80%)
- Anorexia — Very frequent (99-80%)
- Headache — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009210/index) · [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.Glu254Ter |
| Coding change (HGVS c.) | c.759dup |
| MANE Select transcript | [NM_006996](https://www.ncbi.nlm.nih.gov/nuccore/NM_006996) |
| dbSNP | [rs1368720035](https://www.ncbi.nlm.nih.gov/snp/rs1368720035/) |
| Variant type | Duplication |
| Location | chr1:169477202-169477203 (GRCh38) |
| ClinVar | [VCV2734017](https://www.ncbi.nlm.nih.gov/clinvar/variation/2734017/) |

**All HGVS expressions:** `NC_000001.10:g.169446442dup`, `NC_000001.11:g.169477204dup`, `NG_008255.1:g.13768dup`, `NM_001319667.1:c.205-7017dup`, `NM_006996.3:c.759dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 6.01, GERP 1.51, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.852, pLI 2.0312e-06. *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.
- CADD: **PHRED 33.0**. 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 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): grpmax **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/60,000 in the highest group · 3/1,613,918 alleles overall — very rare (popmax 0.005%, 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}

**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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-18.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-18 |

## Associated conditions {#conditions}

[thiamine-responsive megaloblastic anemia syndrome](https://sugi.bio/atlas/disease/thiamine-responsive-megaloblastic-anemia-syndrome/).

**Reported phenotype names (ClinVar):** Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness, not provided, none provided, THIAMINE METABOLISM DYSFUNCTION SYNDROME 1 (MEGALOBLASTIC ANEMIA, DIABETES MELLITUS, AND DEAFNESS TYPE), ROGERS SYNDROME, THIAMINE-RESPONSIVE ANEMIA SYNDROME, THIAMINE-RESPONSIVE MYELODYSPLASIA, Thiamine-Responsive Megaloblastic Anemia Syndrome.

## Similar variants {#similar}

Related SLC19A2 variant pages (same residue, condition, or type): [SLC19A2 p.Tyr81Ter](/variant/slc19a2-p-tyr81ter), [SLC19A2 p.Ala136fs](/variant/slc19a2-p-ala136fs), [SLC19A2 c.1224-4dup](/variant/slc19a2-c-1224-minus-4dup), [SLC19A2 p.Met479fs](/variant/slc19a2-p-met479fs), [SLC19A2 p.Thr495fs](/variant/slc19a2-p-thr495fs), [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).

### 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 2734017). 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.*