Is SLC19A2 p.Arg327Cys (c.979C>T) pathogenic?

SLC19A2 p.Arg327Cys (c.979C>T) is classified Uncertain significance in SLC19A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-17). AlphaMissense: likely benign (0.1209); Ultra-rare (popmax 0.0167%, amr); Associated with thiamine-responsive megaloblastic anemia syndrome.

What condition is associated with SLC19A2 p.Arg327Cys (c.979C>T)?

SLC19A2 p.Arg327Cys (c.979C>T) is associated with thiamine-responsive megaloblastic anemia syndrome (ClinVar).

How common is SLC19A2 p.Arg327Cys (c.979C>T) in the general population?

SLC19A2 p.Arg327Cys (c.979C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about SLC19A2 p.Arg327Cys (c.979C>T)?

AlphaMissense predicts likely benign (score 0.1209) — an in-silico prediction, not a clinical call.

SLC19A2 p.Arg327Cys

Q: How is Thiamine-responsive megaloblastic anemia syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.979C>T · rs151131241 · VCV2419419

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1209 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

thiamine-responsive megaloblastic anemia syndrome

Computational evidence

Protein change
AlphaMissense	0.1209	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -8.47	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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	28.1	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 0.0167% Admixed American · 10/59,988 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00242% 39/1,613,870 alleles · ultra-rare exomes 33/1,461,742 · genomes 6/152,128 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
Middle Eastern	0.0165%	6,078
African / African-American	0.00801%	12,478
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00161%	62,103
South Asian	0.0011%	91,078

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.Arg327Cys
Coding: c.979C>T
MANE Select: NM_006996
dbSNP: rs151131241
Type: single nucleotide variant
Location: chr1:169470015 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 2 PDB
Residue 327: a β-strand

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

Disease context

thiamine-responsive megaloblastic anemia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Thiamine-responsive megaloblastic anemia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

SLC19A2 p.Arg327Leu Uncertain significance ★ ⚠ same residue
SLC19A2 p.Arg327= Likely benign ★ same residue
SLC19A2 c.1223+1G>A Pathogenic ★★ same condition
SLC19A2 c.807+2T>G Likely pathogenic ★★ same condition
SLC19A2 p.Arg162Ter Pathogenic ★★ same condition
SLC19A2 p.Arg397Ter Pathogenic/Likely pathogenic ★★ same condition
SLC19A2 p.Gln233Ter Pathogenic ★★ same condition
SLC19A2 p.Gly105Glu Pathogenic/Likely pathogenic ★★ 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-arg327cys (accessed [today's date]).

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