Is SLC19A3 p.Ser168del (c.503_505del) pathogenic?

SLC19A3 p.Ser168del (c.503505del) is classified Conflicting classifications of pathogenicity in SLC19A3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-02). Ultra-rare (popmax 0.0167%, amr); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Ser168del (c.503_505del)?

SLC19A3 p.Ser168del (c.503_505del) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Ser168del (c.503_505del) in the general population?

SLC19A3 p.Ser168del (c.503_505del) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

How is Thiamine-responsive encephalopathy inherited?

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

SLC19A3 p.Ser168del

c.503_505del · rs763130915 · VCV420629

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

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 · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP -0.59, phastCons 1
Overall
CADD	13.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/60,010 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000867% 14/1,614,132 alleles · ultra-rare exomes 8/1,461,870 · genomes 6/152,262 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,001
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000254%	393,340

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.Ser168del
Coding: c.503_505del
MANE Select: NM_025243
dbSNP: rs763130915
Type: Deletion
Location: chr2:227699210 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 168: a functional site (essential for pyridoxine transport)

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.Ser168Leu Uncertain significance ★ ⚠ same residue
SLC19A3 p.Ser168= Likely benign ★ same residue
SLC19A3 p.His200fs Pathogenic ★★ same condition
SLC19A3 p.Leu161fs Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Lys208fs 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-ser168del (accessed [today's date]).

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