Is SLC19A3 p.Ala165Pro (c.493G>C) pathogenic?

SLC19A3 p.Ala165Pro (c.493G>C) is classified Uncertain significance in SLC19A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-02). AlphaMissense: likely benign (0.3145); Ultra-rare (popmax 0.0165%, mid); Associated with biotin-responsive basal ganglia disease.

What condition is associated with SLC19A3 p.Ala165Pro (c.493G>C)?

SLC19A3 p.Ala165Pro (c.493G>C) is associated with biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Ala165Pro (c.493G>C) in the general population?

SLC19A3 p.Ala165Pro (c.493G>C) is ultra-rare (popmax 0.0165%, mid) (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.Ala165Pro (c.493G>C)?

AlphaMissense predicts likely benign (score 0.3145) — an in-silico prediction, not a clinical call.

SLC19A3 p.Ala165Pro

c.493G>C · rs1272626560 · VCV2715881

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3145 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

biotin-responsive basal ganglia disease

Computational evidence

Protein change
AlphaMissense	0.3145	likely benign
REVEL	0.607	indeterminate
SaProt	LLR -10.99	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.92, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	22.6	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,074 alleles · ultra-rare exomes 2/1,461,844 · genomes 1/152,230 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	0.000169%	589,991

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.Ala165Pro
Coding: c.493G>C
MANE Select: NM_025243
dbSNP: rs1272626560
Type: single nucleotide variant
Location: chr2:227699222 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 165: 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.Ala165Glu Uncertain significance ★★ ⚠ same residue
SLC19A3 p.Ala165= 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

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-ala165pro (accessed [today's date]).

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