Is SLC19A1 p.Arg148His (c.443G>A) pathogenic?

SLC19A1 p.Arg148His (c.443G>A) is classified Uncertain significance in SLC19A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.0839); Very rare (popmax 0.00677%, nfe).

How common is SLC19A1 p.Arg148His (c.443G>A) in the general population?

SLC19A1 p.Arg148His (c.443G>A) is very rare (popmax 0.00677%, nfe) (gnomAD).

What do computational predictors say about SLC19A1 p.Arg148His (c.443G>A)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

SLC19A1 p.Arg148His

c.443G>A · rs570406160 · VCV1441401

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00677%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -2.85	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 -1.4	GERP -3.7
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	16.87	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 0.00677% European (non-Finnish) · 79/1,167,598 alleles

Filtering AF 0.00552% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00511%

Overall 0.00517% 82/1,587,124 alleles · very rare exomes 72/1,434,940 · genomes 10/152,184 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00677%	14,780
Finnishnot grpmax-eligible	0.0033%	30,275
Remaining individualsnot grpmax-eligible	0.00163%	61,480

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.Arg148His
Coding: c.443G>A
MANE Select: NM_194255
dbSNP: rs570406160
Type: single nucleotide variant
Location: chr21:45531895 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 19 PDB
Residue 148: an α-helix

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

Similar variants

SLC19A1 p.Arg148Leu Uncertain significance ★ ⚠ same residue
SLC19A1 p.Arg148= Likely benign ★ 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

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-arg148his (accessed [today's date]).

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