Is SLC19A1 p.Arg456Trp (c.1366C>T) pathogenic?

SLC19A1 p.Arg456Trp (c.1366C>T) is classified Uncertain significance in SLC19A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0885); Very rare (popmax 0.00461%, nfe).

How common is SLC19A1 p.Arg456Trp (c.1366C>T) in the general population?

SLC19A1 p.Arg456Trp (c.1366C>T) is very rare (popmax 0.00461%, nfe) (gnomAD).

What do computational predictors say about SLC19A1 p.Arg456Trp (c.1366C>T)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

SLC19A1 p.Arg456Trp

c.1366C>T · rs773517804 · VCV2517068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00461%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.02	GERP -2.7
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	12.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00461% European (non-Finnish) · 54/1,172,052 alleles

Filtering AF 0.00361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00323%

Overall 0.00389% 62/1,593,484 alleles · very rare exomes 58/1,441,286 · genomes 4/152,198 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00461%	21,705
African / African-American	0.00401%	24,945
Admixed American	0.00361%	27,738
Ashkenazi Jewishnot grpmax-eligible	0.00344%	29,042
Remaining individualsnot grpmax-eligible	0.00162%	61,822
South Asian	0.00113%	88,192

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.Arg456Trp
Coding: c.1366C>T
MANE Select: NM_194255
dbSNP: rs773517804
Type: single nucleotide variant
Location: chr21:45516068 (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

SLC19A1 p.Arg456Gln 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-arg456trp (accessed [today's date]).

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