Is SLC19A2 p.Thr408Ile (c.1223C>T) pathogenic?

SLC19A2 p.Thr408Ile (c.1223C>T) is classified Uncertain significance in SLC19A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-31). AlphaMissense: ambiguous (0.495); Very rare (popmax 0.00534%, afr).

How common is SLC19A2 p.Thr408Ile (c.1223C>T) in the general population?

SLC19A2 p.Thr408Ile (c.1223C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about SLC19A2 p.Thr408Ile (c.1223C>T)?

AlphaMissense predicts ambiguous (score 0.495) — an in-silico prediction, not a clinical call.

SLC19A2 p.Thr408Ile

c.1223C>T · rs765684661 · VCV3253267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.495 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.495	ambiguous
REVEL	0.719	pathogenic-leaning
SaProt	LLR -11.71	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	33.0	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 0.00534% African / African-American · 4/74,842 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00242% 39/1,612,874 alleles · very rare exomes 38/1,460,798 · genomes 1/152,076 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,711
Remaining individualsnot grpmax-eligible	0.0032%	31,219
European (non-Finnish)	0.00263%	38,040
East Asian	0.00223%	44,856
South Asian	0.0011%	90,976

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: SLC19A2
Protein: p.Thr408Ile
Coding: c.1223C>T
MANE Select: NM_006996
dbSNP: rs765684661
Type: single nucleotide variant
Location: chr1:169468644 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 2 PDB
Residue 408: an α-helix

Full SLC19A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SLC19A2 c.1223+1G>A Pathogenic ★★ same type
SLC19A2 c.807+2T>G Likely pathogenic ★★ same type
SLC19A2 p.Arg162Ter Pathogenic ★★ same type
SLC19A2 p.Arg397Ter Pathogenic/Likely pathogenic ★★ same type
SLC19A2 p.Gln233Ter Pathogenic ★★ same type
SLC19A2 p.Glu66Ter Pathogenic ★★ same type
SLC19A2 p.Gly105Glu Pathogenic/Likely pathogenic ★★ same type
SLC19A2 p.Gly172Asp Pathogenic/Likely pathogenic ★★ same type

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/slc19a2-p-thr408ile (accessed [today's date]).

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