Is SLC19A3 p.Ser26fs (c.74dup) pathogenic?

SLC19A3 p.Ser26fs (c.74dup) is classified Pathogenic in SLC19A3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-28). Very rare (popmax 0.00668%, afr); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Ser26fs (c.74dup)?

SLC19A3 p.Ser26fs (c.74dup) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Ser26fs (c.74dup) in the general population?

SLC19A3 p.Ser26fs (c.74dup) is very rare (popmax 0.00668%, afr) (gnomAD).

How is Thiamine-responsive encephalopathy inherited?

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

SLC19A3 p.Ser26fs

c.74dup · rs786205213 · VCV190224

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

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 2 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.7	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% African / African-American · 5/74,902 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00186% 30/1,613,832 alleles · very rare exomes 25/1,461,716 · genomes 5/152,116 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,980
European (non-Finnish)	0.00203%	49,162
Admixed American	0.00167%	59,978

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.Ser26fs
Coding: c.74dup
MANE Select: NM_025243
dbSNP: rs786205213
Type: Duplication
Location: chr2:227702244 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 26: 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.Ser26= Likely benign ★ same residue
SLC19A3 p.Leu360fs Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Met28fs Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Val103fs Pathogenic ★★ same condition
SLC19A3 p.Asn297fs Pathogenic ★ same condition
SLC19A3 p.Asp43fs Pathogenic ★ same condition
SLC19A3 p.Lys44Ter Pathogenic ★ same condition
SLC19A3 p.Tyr462Ter 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-ser26fs (accessed [today's date]).

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