Is SLC19A2 p.Ser163Cys (c.487A>T) pathogenic?

SLC19A2 p.Ser163Cys (c.487A>T) is classified Uncertain significance in SLC19A2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-20). AlphaMissense: likely benign (0.098); Ultra-rare (popmax 0.0362%, sas); Associated with thiamine-responsive megaloblastic anemia syndrome.

What condition is associated with SLC19A2 p.Ser163Cys (c.487A>T)?

SLC19A2 p.Ser163Cys (c.487A>T) is associated with thiamine-responsive megaloblastic anemia syndrome (ClinVar).

How common is SLC19A2 p.Ser163Cys (c.487A>T) in the general population?

SLC19A2 p.Ser163Cys (c.487A>T) is ultra-rare (popmax 0.0362%, sas) (gnomAD).

What do computational predictors say about SLC19A2 p.Ser163Cys (c.487A>T)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

SLC19A2 p.Ser163Cys

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

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

c.487A>T · rs548333207 · VCV293529

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thiamine-responsive megaloblastic anemia syndrome

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.677	pathogenic-leaning
SaProt	LLR -10.93	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 0.94, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	24.2	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 0.0362% South Asian · 33/91,080 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.00706% 114/1,614,162 alleles · ultra-rare exomes 109/1,461,894 · genomes 5/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0362%	2,760
Middle Eastern	0.033%	3,031
Admixed American	0.0133%	7,503
European (non-Finnish)	0.00551%	18,154
Remaining individualsnot grpmax-eligible	0.0048%	20,836
African / African-American	0.004%	25,013

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.Ser163Cys
Coding: c.487A>T
MANE Select: NM_006996
dbSNP: rs548333207
Type: single nucleotide variant
Location: chr1:169477475 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 2 PDB
Residue 163: an α-helix

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.Ser163Asn Uncertain significance ★ ⚠ 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
SLC19A2 p.Gly172Asp 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-ser163cys (accessed [today's date]).

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