Is SLC19A3 p.Thr422Ala (c.1264A>G) pathogenic?

SLC19A3 p.Thr422Ala (c.1264A>G) is classified Pathogenic in SLC19A3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-04-21). AlphaMissense: likely benign (0.2666); Very rare (popmax 0.00223%, eas); Associated with Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type).

How common is SLC19A3 p.Thr422Ala (c.1264A>G) in the general population?

SLC19A3 p.Thr422Ala (c.1264A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SLC19A3 p.Thr422Ala (c.1264A>G)?

AlphaMissense predicts likely benign (score 0.2666) — an in-silico prediction, not a clinical call.

SLC19A3 p.Thr422Ala

Q: What condition is associated with SLC19A3 p.Thr422Ala (c.1264A>G)?

SLC19A3 p.Thr422Ala (c.1264A>G) is associated with Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type), biotin-responsive basal ganglia disease (ClinVar).

c.1264A>G · rs121917884 · VCV4563

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.2666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type)

Computational evidence

Protein change
AlphaMissense	0.2666	likely benign ⚠ discordant with ClinVar
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -12.12	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	26.5	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 0.00223% East Asian · 1/44,878 alleles

Overall 0.000186% 3/1,614,064 alleles · very rare exomes 3/1,461,778 · genomes 0/152,286 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,249
East Asiangrpmax	0.00223%	44,878

Remaining individuals 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.Thr422Ala
Coding: c.1264A>G
MANE Select: NM_025243
dbSNP: rs121917884
Type: single nucleotide variant
Location: chr2:227688216 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 422: a UniProt-annotated variant site (in btbgd); an α-helix

Full SLC19A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type)

Also linked: biotin-responsive basal ganglia disease

Similar variants

SLC19A3 p.Thr422Pro Likely pathogenic ★ 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-thr422ala (accessed [today's date]).

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