Is SLC19A1 p.Arg61Trp (c.181C>T) pathogenic?

SLC19A1 p.Arg61Trp (c.181C>T) is classified Uncertain significance in SLC19A1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-01). AlphaMissense: likely benign (0.168); Ultra-rare (popmax 0.0282%, mid).

How common is SLC19A1 p.Arg61Trp (c.181C>T) in the general population?

SLC19A1 p.Arg61Trp (c.181C>T) is ultra-rare (popmax 0.0282%, mid) (gnomAD).

What do computational predictors say about SLC19A1 p.Arg61Trp (c.181C>T)?

AlphaMissense predicts likely benign (score 0.168) — an in-silico prediction, not a clinical call.

SLC19A1 p.Arg61Trp

c.181C>T · rs142360873 · VCV2198029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.168 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0282%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.168	likely benign
REVEL	0.318	indeterminate
SaProt	LLR -11.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.81	GERP -2.3
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	20.8	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 0.0282% Middle Eastern · 1/3,550 alleles

Filtering AF 0.00698% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00646%

Overall 0.00826% 96/1,162,624 alleles · ultra-rare exomes 85/1,058,864 · genomes 11/103,760 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0282%	3,550
Remaining individualsnot grpmax-eligible	0.0183%	5,459
European (non-Finnish)	0.00855%	11,693
Ashkenazi Jewishnot grpmax-eligible	0.00638%	15,664
African / African-American	0.0062%	16,120
South Asian	0.00483%	20,720
Finnishnot grpmax-eligible	0.00433%	23,070
Admixed American	0.00299%	33,458

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.Arg61Trp
Coding: c.181C>T
MANE Select: NM_194255
dbSNP: rs142360873
Type: single nucleotide variant
Location: chr21:45537779 (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.Lys61Arg 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-arg61trp (accessed [today's date]).

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