Is SLC19A2 p.Gly334Asp (c.1001G>A) pathogenic?

SLC19A2 p.Gly334Asp (c.1001G>A) is classified Pathogenic/Likely pathogenic in SLC19A2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.9649); Very rare (popmax 0.00195%, nfe); Associated with SLC19A2-related disorder.

What condition is associated with SLC19A2 p.Gly334Asp (c.1001G>A)?

SLC19A2 p.Gly334Asp (c.1001G>A) is associated with SLC19A2-related disorder, thiamine-responsive megaloblastic anemia syndrome (ClinVar).

How common is SLC19A2 p.Gly334Asp (c.1001G>A) in the general population?

SLC19A2 p.Gly334Asp (c.1001G>A) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about SLC19A2 p.Gly334Asp (c.1001G>A)?

AlphaMissense predicts likely pathogenic (score 0.9649) — an in-silico prediction, not a clinical call.

SLC19A2 p.Gly334Asp

c.1001G>A · rs199921604 · VCV546109

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9649 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SLC19A2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9649	likely pathogenic ✓ concordant with ClinVar · top 5% in SLC19A2
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -16.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	28.0	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 0.00195% European (non-Finnish) · 23/1,179,924 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00167% 27/1,613,852 alleles · very rare exomes 24/1,461,698 · genomes 3/152,154 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)grpmax	0.00195%	51,301
Admixed American	0.00167%	59,988

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly334Asp
Coding: c.1001G>A
MANE Select: NM_006996
dbSNP: rs199921604
Type: single nucleotide variant
Location: chr1:169469993 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.99 · 2 PDB
Residue 334: an α-helix

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

Disease context

SLC19A2-related disorder

Also linked: thiamine-responsive megaloblastic anemia syndrome

Similar variants

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
SLC19A2 p.Ser143Phe 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-gly334asp (accessed [today's date]).

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