Is SLC19A3 p.Val350Ala (c.1049T>C) pathogenic?

SLC19A3 p.Val350Ala (c.1049T>C) is classified Benign in SLC19A3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0355); Common (popmax 27%, afr) — too common for a highly-penetrant pathogenic allele; Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Val350Ala (c.1049T>C)?

SLC19A3 p.Val350Ala (c.1049T>C) is associated with biotin-responsive basal ganglia disease (ClinVar).

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.Val350Ala (c.1049T>C)?

AlphaMissense predicts likely benign (score 0.0355) — an in-silico prediction, not a clinical call.

SLC19A3 p.Val350Ala

Q: How common is SLC19A3 p.Val350Ala (c.1049T>C) in the general population?

SLC19A3 p.Val350Ala (c.1049T>C) is common (popmax 27%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1049T>C · rs34507036 · VCV130320

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0355 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 27%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.0355	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -5.49	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 3.9	GERP -3.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	10.17	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 27% African / African-American · 20,215/74,954 alleles

Filtering AF 26.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 26.5%

Overall 2.41% 38,918/1,614,086 alleles · common exomes 26,168/1,461,884 · genomes 12,750/152,202 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	27%	4
Remaining individualsnot grpmax-eligible	3%	33
Middle Eastern	2.75%	36
Admixed American	2.35%	42
East Asian	2.25%	44
European (non-Finnish)	1.13%	89
Ashkenazi Jewishnot grpmax-eligible	1.08%	93
South Asian	0.569%	176
Amishnot grpmax-eligible	0.548%	182
Finnishnot grpmax-eligible	0.136%	736

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.Val350Ala
Coding: c.1049T>C
MANE Select: NM_025243
dbSNP: rs34507036
Type: single nucleotide variant
Location: chr2:227696012 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 350: a UniProt-annotated variant site (in); 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.Val350= 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-val350ala (accessed [today's date]).

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