Is SLC19A2 c.-4C>T pathogenic?

SLC19A2 c.-4C>T is classified Benign in SLC19A2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-11-26). Common (popmax 29.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with thiamine-responsive megaloblastic anemia syndrome.

What condition is associated with SLC19A2 c.-4C>T?

SLC19A2 c.-4C>T is associated with thiamine-responsive megaloblastic anemia syndrome (ClinVar).

SLC19A2 c.-4C>T

Q: How common is SLC19A2 c.-4C>T in the general population?

SLC19A2 c.-4C>T is common (popmax 29.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Thiamine-responsive megaloblastic anemia syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

rs2072757 · VCV130317

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 29.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

thiamine-responsive megaloblastic anemia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -3.3, phastCons 0.004
Overall
CADD	15.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 29.3% African / African-American · 21,235/72,502 alleles

Filtering AF 29% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.8%

Overall 12.4% 189,612/1,529,132 alleles · common exomes 164,237/1,377,168 · genomes 25,375/151,964 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	29.3%	3
Ashkenazi Jewishnot grpmax-eligible	27.8%	4
South Asian	19.8%	5
Middle Eastern	18.9%	5
Amishnot grpmax-eligible	15.8%	6
Remaining individualsnot grpmax-eligible	14.7%	7
Admixed American	14%	7
East Asian	10.9%	9
European (non-Finnish)	10.5%	10
Finnishnot grpmax-eligible	6.43%	16

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SLC19A2
Coding: c.-4C>T
MANE Select: NM_006996
dbSNP: rs2072757
Type: single nucleotide variant
Location: chr1:169485770 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 2 PDB

Full SLC19A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thiamine-responsive megaloblastic anemia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Thiamine-responsive megaloblastic anemia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

SLC19A2 c.1223+1G>A Pathogenic ★★ same condition
SLC19A2 c.807+2T>G Likely pathogenic ★★ same condition
SLC19A2 p.Arg162Ter Pathogenic ★★ same condition
SLC19A2 p.Arg397Ter Pathogenic/Likely pathogenic ★★ same condition
SLC19A2 p.Gln233Ter Pathogenic ★★ same condition
SLC19A2 p.Gly105Glu Pathogenic/Likely pathogenic ★★ same condition
SLC19A2 p.Gly172Asp Pathogenic/Likely pathogenic ★★ same condition
SLC19A2 p.Gly334Asp Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/slc19a2-c-minus-4c-t (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown