Is SLC19A3 p.Val319Ile (c.955G>A) pathogenic?

SLC19A3 p.Val319Ile (c.955G>A) is classified Uncertain significance in SLC19A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). AlphaMissense: likely benign (0.1302); Very rare (popmax 0.00668%, eas); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Val319Ile (c.955G>A)?

SLC19A3 p.Val319Ile (c.955G>A) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Val319Ile (c.955G>A) in the general population?

SLC19A3 p.Val319Ile (c.955G>A) is very rare (popmax 0.00668%, 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.Val319Ile (c.955G>A)?

AlphaMissense predicts likely benign (score 0.1302) — an in-silico prediction, not a clinical call.

SLC19A3 p.Val319Ile

c.955G>A · rs372511010 · VCV1479652

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.1302	likely benign
REVEL	0.599	indeterminate
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	24.1	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 0.00668% East Asian · 3/44,892 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00031% 5/1,613,696 alleles · very rare exomes 4/1,461,486 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,964
African / African-American	0.00133%	74,932
European (non-Finnish)	8.48e-05%	1,179,935

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.Val319Ile
Coding: c.955G>A
MANE Select: NM_025243
dbSNP: rs372511010
Type: single nucleotide variant
Location: chr2:227698760 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 319: 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.Val319= Likely benign ★★ same residue
SLC19A3 p.Val319Leu 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-val319ile (accessed [today's date]).

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