Is SLC19A2 p.Ala467Thr (c.1399G>A) pathogenic?

SLC19A2 p.Ala467Thr (c.1399G>A) is classified Uncertain significance in SLC19A2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1748); Ultra-rare (popmax 0.0493%, mid); Associated with thiamine-responsive megaloblastic anemia syndrome.

What condition is associated with SLC19A2 p.Ala467Thr (c.1399G>A)?

SLC19A2 p.Ala467Thr (c.1399G>A) is associated with thiamine-responsive megaloblastic anemia syndrome (ClinVar).

How common is SLC19A2 p.Ala467Thr (c.1399G>A) in the general population?

SLC19A2 p.Ala467Thr (c.1399G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about SLC19A2 p.Ala467Thr (c.1399G>A)?

AlphaMissense predicts likely benign (score 0.1748) — an in-silico prediction, not a clinical call.

SLC19A2 p.Ala467Thr

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

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

c.1399G>A · rs147884156 · VCV2145562

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1748 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thiamine-responsive megaloblastic anemia syndrome

Computational evidence

Protein change
AlphaMissense	0.1748	likely benign
REVEL	0.396	indeterminate
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Pangolin	Δ0.35	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 3.7	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	22.1	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.0149% 240/1,613,804 alleles · ultra-rare exomes 227/1,461,784 · genomes 13/152,020 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
European (non-Finnish)	0.0185%	5,413
Remaining individualsnot grpmax-eligible	0.0096%	10,413
South Asian	0.00769%	13,011
Finnishnot grpmax-eligible	0.00313%	31,983
African / African-American	0.00267%	37,426
East Asian	0.00223%	44,886
Admixed American	0.00167%	59,980

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.Ala467Thr
Coding: c.1399G>A
MANE Select: NM_006996
dbSNP: rs147884156
Type: single nucleotide variant
Location: chr1:169465944 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 2 PDB
Residue 467: 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

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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
SLC19A2 p.Gly334Asp 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-ala467thr (accessed [today's date]).

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