Is SLC19A3 p.Lys208fs (c.623_626del) pathogenic?

SLC19A3 p.Lys208fs (c.623626del) is classified Pathogenic/Likely pathogenic in SLC19A3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-21). Very rare (popmax 0.000254%, nfe); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Lys208fs (c.623_626del)?

SLC19A3 p.Lys208fs (c.623_626del) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Lys208fs (c.623_626del) in the general population?

SLC19A3 p.Lys208fs (c.623_626del) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Thiamine-responsive encephalopathy inherited?

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

SLC19A3 p.Lys208fs

c.623_626del · rs2470573380 · VCV1899857

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.8	GERP -0.54

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,048 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,226 alleles · very rare exomes 4/1,461,890 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)grpmax	0.000254%	393,349

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Lys208fs
Coding: c.623_626del
MANE Select: NM_025243
dbSNP: rs2470573380
Type: Deletion
Location: chr2:227699089 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB

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.Lys208Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
SLC19A3 p.Lys208Gln Uncertain significance ★ ⚠ same residue
SLC19A3 p.Lys208Glu Uncertain significance ★ ⚠ same residue
SLC19A3 p.His200fs Pathogenic ★★ same condition
SLC19A3 p.Leu161fs Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Tyr38fs Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Val299fs Pathogenic ★★ same condition
SLC19A3 p.Val58fs 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-lys208fs (accessed [today's date]).

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