Is SLC19A3 p.Ile378Val (c.1132A>G) pathogenic?

SLC19A3 p.Ile378Val (c.1132A>G) is classified Benign/Likely benign in SLC19A3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0691); Low-frequency (popmax 2.25%, eas); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Ile378Val (c.1132A>G)?

SLC19A3 p.Ile378Val (c.1132A>G) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Ile378Val (c.1132A>G) in the general population?

SLC19A3 p.Ile378Val (c.1132A>G) is low-frequency (popmax 2.25%, 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.Ile378Val (c.1132A>G)?

AlphaMissense predicts likely benign (score 0.0691) — an in-silico prediction, not a clinical call.

SLC19A3 p.Ile378Val

c.1132A>G · rs117864472 · VCV334878

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0691 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.25%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.0691	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -6.06	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 -0.44	GERP -3.5
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	1.358	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 2.25% East Asian · 1,009/44,876 alleles

Filtering AF 2.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.09%

Overall 0.0745% 1,203/1,614,094 alleles · low-frequency exomes 1,065/1,461,874 · genomes 138/152,220 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	2.25%	44
Amishnot grpmax-eligible	0.439%	228
South Asian	0.115%	867
Remaining individualsnot grpmax-eligible	0.0816%	1,226
Middle Eastern	0.0165%	6,050
Admixed American	0.00667%	15,002
African / African-American	0.004%	25,007
European (non-Finnish)	0.0022%	45,385

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.Ile378Val
Coding: c.1132A>G
MANE Select: NM_025243
dbSNP: rs117864472
Type: single nucleotide variant
Location: chr2:227695929 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 378: 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 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
SLC19A3 p.Ser181Pro 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-ile378val (accessed [today's date]).

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