Is SLC19A2 p.Glu254Ter (c.759dup) pathogenic?

SLC19A2 p.Glu254Ter (c.759dup) is classified Pathogenic in SLC19A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-18). Very rare (popmax 0.005%, amr); Associated with thiamine-responsive megaloblastic anemia syndrome.

What condition is associated with SLC19A2 p.Glu254Ter (c.759dup)?

SLC19A2 p.Glu254Ter (c.759dup) is associated with thiamine-responsive megaloblastic anemia syndrome (ClinVar).

How common is SLC19A2 p.Glu254Ter (c.759dup) in the general population?

SLC19A2 p.Glu254Ter (c.759dup) is very rare (popmax 0.005%, amr) (gnomAD).

SLC19A2 p.Glu254Ter

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

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

c.759dup · rs1368720035 · VCV2734017

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

thiamine-responsive megaloblastic anemia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,000 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,918 alleles · very rare exomes 2/1,461,734 · genomes 1/152,184 · joint denominator

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.Glu254Ter
Coding: c.759dup
MANE Select: NM_006996
dbSNP: rs1368720035
Type: Duplication
Location: chr1:169477202 (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

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.Tyr81Ter Pathogenic ★★ same condition
SLC19A2 p.Ala136fs Pathogenic ★ same condition
SLC19A2 c.1224-4dup Conflicting classifications of pathogenicity ★ same condition
SLC19A2 p.Met479fs Uncertain significance ★ same condition
SLC19A2 p.Thr495fs Uncertain significance ★ same condition
SLC19A2 c.1223+1G>A Pathogenic ★★ same condition
SLC19A2 c.807+2T>G Likely pathogenic ★★ same condition
SLC19A2 p.Arg162Ter 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-glu254ter (accessed [today's date]).

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