Is SLC19A3 p.Ser488Thr (c.1463G>C) pathogenic?

SLC19A3 p.Ser488Thr (c.1463G>C) is classified Uncertain significance in SLC19A3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-09). AlphaMissense: likely benign (0.0706); Ultra-rare (popmax 0.0495%, mid); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Ser488Thr (c.1463G>C)?

SLC19A3 p.Ser488Thr (c.1463G>C) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Ser488Thr (c.1463G>C) in the general population?

SLC19A3 p.Ser488Thr (c.1463G>C) is ultra-rare (popmax 0.0495%, mid) (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.Ser488Thr (c.1463G>C)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

SLC19A3 p.Ser488Thr

c.1463G>C · rs540774490 · VCV841842

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -1.4
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	0.147	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.000992% 16/1,613,252 alleles · ultra-rare exomes 13/1,460,944 · genomes 3/152,308 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
Remaining individualsnot grpmax-eligible	0.0032%	31,235
African / African-American	0.00133%	75,018
European (non-Finnish)	0.000848%	117,948

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.Ser488Thr
Coding: c.1463G>C
MANE Select: NM_025243
dbSNP: rs540774490
Type: single nucleotide variant
Location: chr2:227687425 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 488: the 'disordered' region

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.Ser488= Likely benign ★ 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
SLC19A3 p.Met1Leu 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-ser488thr (accessed [today's date]).

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