Is SLC19A3 p.Ala150Thr (c.448G>A) pathogenic?

SLC19A3 p.Ala150Thr (c.448G>A) is classified Uncertain significance in SLC19A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-23). AlphaMissense: likely pathogenic (0.6262); Ultra-rare (popmax 0.0891%, eas); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Ala150Thr (c.448G>A)?

SLC19A3 p.Ala150Thr (c.448G>A) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Ala150Thr (c.448G>A) in the general population?

SLC19A3 p.Ala150Thr (c.448G>A) is ultra-rare (popmax 0.0891%, eas) (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.Ala150Thr (c.448G>A)?

AlphaMissense predicts likely pathogenic (score 0.6262) — an in-silico prediction, not a clinical call.

SLC19A3 p.Ala150Thr

c.448G>A · rs117013375 · VCV1064368

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6262 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0891%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.6262	likely pathogenic
REVEL	0.555	indeterminate
SaProt	LLR -10.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0891% East Asian · 40/44,876 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0596%

Overall 0.00347% 56/1,614,044 alleles · ultra-rare exomes 51/1,461,762 · genomes 5/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0891%	1,122
African / African-American	0.004%	25,015
Admixed American	0.00333%	30,003
South Asian	0.0011%	91,082
European (non-Finnish)	0.000847%	117,995

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.Ala150Thr
Coding: c.448G>A
MANE Select: NM_025243
dbSNP: rs117013375
Type: single nucleotide variant
Location: chr2:227699267 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 150: 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.Ala150Val Likely pathogenic ★ same residue
SLC19A3 p.Ala150Pro Uncertain significance ★ ⚠ 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-ala150thr (accessed [today's date]).

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