Is SLC19A3 p.Asn173Ser (c.518A>G) pathogenic?

SLC19A3 p.Asn173Ser (c.518A>G) is classified Uncertain significance in SLC19A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-18). AlphaMissense: likely benign (0.1315); Very rare (popmax 0.00134%, afr); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Asn173Ser (c.518A>G)?

SLC19A3 p.Asn173Ser (c.518A>G) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Asn173Ser (c.518A>G) in the general population?

SLC19A3 p.Asn173Ser (c.518A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Thiamine-responsive encephalopathy inherited?

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

What do computational predictors say about SLC19A3 p.Asn173Ser (c.518A>G)?

AlphaMissense predicts likely benign (score 0.1315) — an in-silico prediction, not a clinical call.

SLC19A3 p.Asn173Ser

c.518A>G · rs1279277694 · VCV970749

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.1315	likely benign
REVEL	0.561	indeterminate
SaProt	LLR -11.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	16.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,836 alleles

Overall 0.000248% 4/1,613,798 alleles · very rare exomes 3/1,461,880 · genomes 1/151,918 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,333
African / African-Americangrpmax	0.00134%	74,836

Finnish 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.Asn173Ser
Coding: c.518A>G
MANE Select: NM_025243
dbSNP: rs1279277694
Type: single nucleotide variant
Location: chr2:227699197 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 173: a functional site (essential for pyridoxine transport); 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.Asn173= Likely benign ★★ same residue
SLC19A3 p.Asn173Asp Likely pathogenic ★ 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

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-asn173ser (accessed [today's date]).

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