Is SLC19A2 p.Ile331Leu (c.991A>C) pathogenic?

SLC19A2 p.Ile331Leu (c.991A>C) is classified Uncertain significance in SLC19A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.1213); Very rare (popmax 0.00364%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SLC19A2 p.Ile331Leu (c.991A>C)?

SLC19A2 p.Ile331Leu (c.991A>C) is associated with Inborn genetic diseases, thiamine-responsive megaloblastic anemia syndrome (ClinVar).

How common is SLC19A2 p.Ile331Leu (c.991A>C) in the general population?

SLC19A2 p.Ile331Leu (c.991A>C) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about SLC19A2 p.Ile331Leu (c.991A>C)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

SLC19A2 p.Ile331Leu

c.991A>C · VCV3599990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -8.81	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 -0.23	GERP -0.27, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	20.6	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 0.00364% European (non-Finnish) · 43/1,179,908 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00273% 44/1,613,808 alleles · very rare exomes 42/1,461,696 · genomes 2/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,440
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Ile331Leu
Coding: c.991A>C
MANE Select: NM_006996
Type: single nucleotide variant
Location: chr1:169470003 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thiamine-responsive megaloblastic anemia syndrome

Similar variants

SLC19A2 p.Ile331Phe 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-ile331leu (accessed [today's date]).

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