# NM_006996.3(SLC19A2):c.639G>A (p.Lys213=)

https://sugi.bio/variant/slc19a2-p-lys213

## Summary

**SLC19A2 p.Lys213= (c.639G>A)** is classified **Conflicting classifications of pathogenicity** in SLC19A2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). Rare (popmax 0.511%, mid); Associated with thiamine-responsive megaloblastic anemia syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs137970656 · 7 submitters · 1 linked condition · rare (popmax 0.511%, mid)

## For patients & families {#patients}

This is a change in the SLC19A2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 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.Lys213= |
| Coding change (HGVS c.) | c.639G>A |
| MANE Select transcript | [NM_006996](https://www.ncbi.nlm.nih.gov/nuccore/NM_006996) |
| dbSNP | [rs137970656](https://www.ncbi.nlm.nih.gov/snp/rs137970656/) |
| Variant type | single nucleotide variant |
| Location | chr1:169477323-169477323 (GRCh38) |
| ClinVar | [VCV293527](https://www.ncbi.nlm.nih.gov/clinvar/variation/293527/) |

**All HGVS expressions:** `NC_000001.10:g.169446561C>T`, `NC_000001.11:g.169477323C>T`, `NG_008255.1:g.13648G>A`, `NM_001319667.1:c.205-7137G>A`, `NM_006996.3:c.639G>A`

## 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 1.108, GERP 1.25, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.776**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, C>A, IS in the release and scores Δ0.29 acceptor loss, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.511%** (mid) · FAF95 0.37% · FAF99 0.322% · 31/6,062 in the highest group · 1,581/1,614,174 alleles overall — rare (popmax 0.511%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 2.86% | 35 |
| Middle Eastern (grpmax) | 0.511% | 196 |
| Remaining individuals (not grpmax-eligible) | 0.27% | 370 |
| Admixed American | 0.11% | 909 |
| European (non-Finnish) | 0.0355% | 2,816 |
| South Asian | 0.0307% | 3,253 |
| African / African-American | 0.0293% | 3,411 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (3 Benign, 3 Likely benign, 1 Uncertain significance).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2019-02-25 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-06-25 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2024-06-17 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |

## 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, not specified, AllHighlyPenetrant, none provided, THIAMINE METABOLISM DYSFUNCTION SYNDROME 1 (MEGALOBLASTIC ANEMIA, DIABETES MELLITUS, AND DEAFNESS TYPE), Thiamine-Responsive Megaloblastic Anemia Syndrome, ROGERS SYNDROME, THIAMINE-RESPONSIVE ANEMIA SYNDROME, THIAMINE-RESPONSIVE MYELODYSPLASIA.

## 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.Gly105Glu](/variant/slc19a2-p-gly105glu), [SLC19A2 p.Gly172Asp](/variant/slc19a2-p-gly172asp), [SLC19A2 p.Gly334Asp](/variant/slc19a2-p-gly334asp).

### 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 293527). 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.*