Is SLC19A3 p.Pro133= (c.399C>G) pathogenic?

SLC19A3 p.Pro133= (c.399C>G) is classified Conflicting classifications of pathogenicity in SLC19A3 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-04). Ultra-rare (popmax 0.0955%, nfe); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Pro133= (c.399C>G)?

SLC19A3 p.Pro133= (c.399C>G) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Pro133= (c.399C>G) in the general population?

SLC19A3 p.Pro133= (c.399C>G) is ultra-rare (popmax 0.0955%, nfe) (gnomAD).

How is Thiamine-responsive encephalopathy inherited?

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

SLC19A3 p.Pro133=

c.399C>G · rs138363524 · VCV290414

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0955%, nfe)

Conditions

biotin-responsive basal ganglia disease

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 -6.5	GERP -3.7
Overall
CADD	0.099	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0955% European (non-Finnish) · 1,127/1,180,034 alleles

Filtering AF 0.0908% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0889%

Overall 0.0754% 1,217/1,614,040 alleles · ultra-rare exomes 1,152/1,461,882 · genomes 65/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0955%	1,047
Remaining individualsnot grpmax-eligible	0.0944%	1,059
African / African-American	0.0254%	3,944
Admixed American	0.0133%	7,499
Finnishnot grpmax-eligible	0.00625%	16,007

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: SLC19A3
Protein: p.Pro133=
Coding: c.399C>G
MANE Select: NM_025243
dbSNP: rs138363524
Type: single nucleotide variant
Location: chr2:227699316 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 133: an α-helix

Full SLC19A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

biotin-responsive basal ganglia disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Thiamine-responsive encephalopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent

Similar variants

SLC19A3 p.Pro133Leu Uncertain significance ★★ ⚠ same residue
SLC19A3 c.1172+1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 c.1172+2T>G Pathogenic ★★ same condition
SLC19A3 c.1173-1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 c.151-1G>C Likely pathogenic ★★ same condition
SLC19A3 c.980-14A>G Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Gly23Val Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Met1Leu 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/slc19a3-p-pro133 (accessed [today's date]).

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