Is SLC19A2 p.Arg275Cys (c.823C>T) pathogenic?

SLC19A2 p.Arg275Cys (c.823C>T) is classified Uncertain significance in SLC19A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-18). AlphaMissense: likely benign (0.0915); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with SLC19A2 p.Arg275Cys (c.823C>T)?

SLC19A2 p.Arg275Cys (c.823C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SLC19A2 p.Arg275Cys (c.823C>T) in the general population?

SLC19A2 p.Arg275Cys (c.823C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about SLC19A2 p.Arg275Cys (c.823C>T)?

AlphaMissense predicts likely benign (score 0.0915) — an in-silico prediction, not a clinical call.

SLC19A2 p.Arg275Cys

c.823C>T · rs138868959 · VCV2056567

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0915 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0915	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -4.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	22.5	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00204% 33/1,613,768 alleles · ultra-rare exomes 30/1,461,662 · genomes 3/152,106 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00549%	18,214
Remaining individualsnot grpmax-eligible	0.0048%	20,826
Admixed American	0.00334%	29,975
East Asian	0.00223%	44,890
European (non-Finnish)	0.0017%	58,995
African / African-American	0.00134%	74,876

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: SLC19A2
Protein: p.Arg275Cys
Coding: c.823C>T
MANE Select: NM_006996
dbSNP: rs138868959
Type: single nucleotide variant
Location: chr1:169470171 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 2 PDB

Full SLC19A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC19A2 p.Arg275His Uncertain significance ★ ⚠ same residue
SLC19A2 p.Arg275Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SLC19A2 p.Arg275= Likely benign ★ same residue
SLC19A2 p.Ala201Gly Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Ala431Ser Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Glu321Lys Uncertain significance ★★ same condition
SLC19A2 p.Gly184Ser Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Gly235Ser Uncertain significance ★★ ⚠ same condition

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/slc19a2-p-arg275cys (accessed [today's date]).

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