Is SLC19A3 p.Gly443Val (c.1328G>T) pathogenic?

SLC19A3 p.Gly443Val (c.1328G>T) is classified Uncertain significance in SLC19A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: ambiguous (0.451); Very rare (popmax 0.00133%, afr); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Gly443Val (c.1328G>T)?

SLC19A3 p.Gly443Val (c.1328G>T) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Gly443Val (c.1328G>T) in the general population?

SLC19A3 p.Gly443Val (c.1328G>T) is very rare (popmax 0.00133%, 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.Gly443Val (c.1328G>T)?

AlphaMissense predicts ambiguous (score 0.451) — an in-silico prediction, not a clinical call.

SLC19A3 p.Gly443Val

c.1328G>T · rs1695064805 · VCV940121

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.451 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.451	ambiguous
REVEL	0.727	pathogenic-leaning
SaProt	LLR -13.73	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.93, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	29.5	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 0.00133% African / African-American · 1/74,984 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,822 alleles · very rare exomes 3/1,461,644 · genomes 0/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,984
European (non-Finnish)	0.00017%	589,957

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.Gly443Val
Coding: c.1328G>T
MANE Select: NM_025243
dbSNP: rs1695064805
Type: single nucleotide variant
Location: chr2:227687560 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 443: 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.Gly443= 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-gly443val (accessed [today's date]).

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