Is SLC19A2 p.Trp250Cys (c.750G>C) pathogenic?

SLC19A2 p.Trp250Cys (c.750G>C) is classified Uncertain significance in SLC19A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-09). AlphaMissense: ambiguous (0.3479); Ultra-rare (popmax 0.0133%, amr).

How common is SLC19A2 p.Trp250Cys (c.750G>C) in the general population?

SLC19A2 p.Trp250Cys (c.750G>C) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about SLC19A2 p.Trp250Cys (c.750G>C)?

AlphaMissense predicts ambiguous (score 0.3479) — an in-silico prediction, not a clinical call.

SLC19A2 p.Trp250Cys

c.750G>C · rs74315374 · VCV2154103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3479 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Computational evidence

Protein change
AlphaMissense	0.3479	ambiguous
REVEL	0.357	indeterminate
SaProt	LLR -3.77	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	22.9	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 0.0133% Admixed American · 8/59,988 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000744% 12/1,613,946 alleles · ultra-rare exomes 8/1,461,788 · genomes 4/152,158 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.000254%	393,337

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.Trp250Cys
Coding: c.750G>C
MANE Select: NM_006996
dbSNP: rs74315374
Type: single nucleotide variant
Location: chr1:169477212 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 2 PDB

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

Similar variants

SLC19A2 p.Trp250Ter Pathogenic/Likely pathogenic ★★ same residue
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

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-trp250cys (accessed [today's date]).

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