Is SLC19A1 p.Cys458Gly (c.1372T>G) pathogenic?

SLC19A1 p.Cys458Gly (c.1372T>G) is classified Benign in SLC19A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0798); Very rare (popmax 0.00912%, amr).

How common is SLC19A1 p.Cys458Gly (c.1372T>G) in the general population?

SLC19A1 p.Cys458Gly (c.1372T>G) is very rare (popmax 0.00912%, amr) (gnomAD).

What do computational predictors say about SLC19A1 p.Cys458Gly (c.1372T>G)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

SLC19A1 p.Cys458Gly

c.1372T>G · VCV3673263

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00912%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -10.48	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.27	GERP -0.59
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	1.092	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 0.00912% Admixed American · 5/54,830 alleles

Filtering AF 0.00389% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00355%

Overall 0.0229% 364/1,591,026 alleles · very rare exomes 316/1,438,874 · genomes 48/152,152 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.904%	111
Remaining individualsnot grpmax-eligible	0.0632%	1,583
Admixed Americangrpmax	0.00912%	10,966
European (non-Finnish)	0.00495%	20,188

Ashkenazi Jewish 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: SLC19A1
Protein: p.Cys458Gly
Coding: c.1372T>G
MANE Select: NM_194255
Type: single nucleotide variant
Location: chr21:45516062 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 19 PDB

Full SLC19A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RFC1 p.Lys458Arg Uncertain significance ★ ⚠ same residue
COL18A1 p.Arg1081Ter Pathogenic/Likely pathogenic ★★ same type
COL18A1 p.Arg915Ter Pathogenic/Likely pathogenic ★★ same type
RFC1 p.Arg383Ter Pathogenic/Likely pathogenic ★★ same type
COL18A1 c.*30G>A Uncertain significance ★★ same type
COL18A1 p.Ala1089Thr Uncertain significance ★★ ⚠ same type
COL18A1 p.Ala1254Val Uncertain significance ★★ ⚠ same type
COL18A1 p.Arg1081Gln Uncertain significance ★★ ⚠ 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/slc19a1-p-cys458gly (accessed [today's date]).

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