Is SLC19A3 p.Ala371Val (c.1112C>T) pathogenic?

SLC19A3 p.Ala371Val (c.1112C>T) is classified Conflicting classifications of pathogenicity in SLC19A3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0641); Ultra-rare (popmax 0.0426%, afr); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Ala371Val (c.1112C>T)?

SLC19A3 p.Ala371Val (c.1112C>T) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Ala371Val (c.1112C>T) in the general population?

SLC19A3 p.Ala371Val (c.1112C>T) is ultra-rare (popmax 0.0426%, 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.Ala371Val (c.1112C>T)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

SLC19A3 p.Ala371Val

c.1112C>T · rs142166552 · VCV215156

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0426%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -7.45	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 -1.2	GERP -3.5
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	0.863	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 0.0426% African / African-American · 32/75,030 alleles

Filtering AF 0.0332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0322%

Overall 0.0354% 571/1,614,104 alleles · ultra-rare exomes 519/1,461,876 · genomes 52/152,228 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.206%	485
Remaining individualsnot grpmax-eligible	0.0528%	1,894
African / African-Americangrpmax	0.0426%	2,345
European (non-Finnish)	0.0361%	2,770
Admixed American	0.0117%	8,572
South Asian	0.011%	9,107
Finnishnot grpmax-eligible	0.00312%	32,007

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala371Val
Coding: c.1112C>T
MANE Select: NM_025243
dbSNP: rs142166552
Type: single nucleotide variant
Location: chr2:227695949 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 371: 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.Ala371= 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-ala371val (accessed [today's date]).

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