Is SLC19A1 p.Arg456Gln (c.1367G>A) pathogenic?

SLC19A1 p.Arg456Gln (c.1367G>A) is classified Uncertain significance in SLC19A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-20). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0498%, eas).

How common is SLC19A1 p.Arg456Gln (c.1367G>A) in the general population?

SLC19A1 p.Arg456Gln (c.1367G>A) is ultra-rare (popmax 0.0498%, eas) (gnomAD).

What do computational predictors say about SLC19A1 p.Arg456Gln (c.1367G>A)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

SLC19A1 p.Arg456Gln

c.1367G>A · rs59841046 · VCV1980513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0498%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -7.99	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 -2.4	GERP -2.7
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	4.393	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 0.0498% East Asian · 22/44,136 alleles

Filtering AF 0.0337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0285%

Overall 0.00289% 46/1,593,398 alleles · ultra-rare exomes 42/1,441,094 · genomes 4/152,304 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0498%	2,006
Remaining individualsnot grpmax-eligible	0.00323%	30,913
African / African-American	0.00267%	37,489
South Asian	0.00227%	44,085
Admixed American	0.0018%	55,446
European (non-Finnish)	0.00145%	68,938

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.Arg456Gln
Coding: c.1367G>A
MANE Select: NM_194255
dbSNP: rs59841046
Type: single nucleotide variant
Location: chr21:45516067 (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.Arg456Trp 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-arg456gln (accessed [today's date]).

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