Is SLC19A3 p.Val174Ile (c.520G>A) pathogenic?

SLC19A3 p.Val174Ile (c.520G>A) is classified Benign in SLC19A3 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0863); Common (popmax 10.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Val174Ile (c.520G>A)?

SLC19A3 p.Val174Ile (c.520G>A) 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.Val174Ile (c.520G>A)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

SLC19A3 p.Val174Ile

Q: How common is SLC19A3 p.Val174Ile (c.520G>A) in the general population?

SLC19A3 p.Val174Ile (c.520G>A) is common (popmax 10.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.520G>A · rs59736804 · VCV130324

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.6%, 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	0.0863	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -7.41	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 1.6	GERP 1.9, phastCons 0.83
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	12.93	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 10.6% African / African-American · 7,929/74,980 alleles

Filtering AF 10.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.3%

Overall 0.558% 8,999/1,614,040 alleles · common exomes 4,399/1,461,886 · genomes 4,600/152,154 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.6%	9
Admixed American	0.72%	139
Remaining individualsnot grpmax-eligible	0.71%	141
Middle Eastern	0.412%	242
Ashkenazi Jewishnot grpmax-eligible	0.111%	897
South Asian	0.0187%	5,357
European (non-Finnish)	0.01%	10,000
East Asian	0.00223%	44,874

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.Val174Ile
Coding: c.520G>A
MANE Select: NM_025243
dbSNP: rs59736804
Type: single nucleotide variant
Location: chr2:227699195 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 174: 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.Val174= 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-val174ile (accessed [today's date]).

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