Is SLC19A3 p.Met28fs (c.81_82dup) pathogenic?

SLC19A3 p.Met28fs (c.8182dup) is classified Pathogenic/Likely pathogenic in SLC19A3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-08). Very rare (popmax 0.00382%, nfe); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Met28fs (c.81_82dup)?

SLC19A3 p.Met28fs (c.81_82dup) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Met28fs (c.81_82dup) in the general population?

SLC19A3 p.Met28fs (c.81_82dup) is very rare (popmax 0.00382%, nfe) (gnomAD).

How is Thiamine-responsive encephalopathy inherited?

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

SLC19A3 p.Met28fs

c.81_82dup · rs775835429 · VCV369672

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00382%, 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 2 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9	GERP 1.9, phastCons 1
Overall
CADD	32.0	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 0.00382% European (non-Finnish) · 45/1,179,348 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00279% 45/1,613,316 alleles · very rare exomes 43/1,461,124 · genomes 2/152,192 · joint denominator

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.Met28fs
Coding: c.81_82dup
MANE Select: NM_025243
dbSNP: rs775835429
Type: Duplication
Location: chr2:227702236 (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.Met28del Uncertain significance ★ same residue
SLC19A3 p.Met28Ile Uncertain significance ★ same residue
SLC19A3 p.Leu360fs Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Ser26fs 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

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-met28fs (accessed [today's date]).

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