Is SLC19A3 p.Phe186Ser (c.557T>C) pathogenic?

SLC19A3 p.Phe186Ser (c.557T>C) is classified Conflicting classifications of pathogenicity in SLC19A3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1028); Ultra-rare (popmax 0.0746%, afr); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Phe186Ser (c.557T>C)?

SLC19A3 p.Phe186Ser (c.557T>C) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Phe186Ser (c.557T>C) in the general population?

SLC19A3 p.Phe186Ser (c.557T>C) is ultra-rare (popmax 0.0746%, 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.Phe186Ser (c.557T>C)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

SLC19A3 p.Phe186Ser

c.557T>C · rs116533505 · VCV215151

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0746%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP -2.5, phastCons 0.86
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	9.177	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 0.0746% African / African-American · 56/75,030 alleles

Filtering AF 0.059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00396% 64/1,614,154 alleles · ultra-rare exomes 37/1,461,890 · genomes 27/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0746%	1,340
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.00333%	30,001
European (non-Finnish)	8.47e-05%	1,180,038

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.Phe186Ser
Coding: c.557T>C
MANE Select: NM_025243
dbSNP: rs116533505
Type: single nucleotide variant
Location: chr2:227699158 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 186: 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.Phe186Leu 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
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-phe186ser (accessed [today's date]).

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