Is SLC19A3 p.Val109Ala (c.326T>C) pathogenic?

SLC19A3 p.Val109Ala (c.326T>C) is classified Uncertain significance in SLC19A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: likely benign (0.1284); Very rare (popmax 0.0011%, sas).

How common is SLC19A3 p.Val109Ala (c.326T>C) in the general population?

SLC19A3 p.Val109Ala (c.326T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SLC19A3 p.Val109Ala (c.326T>C)?

AlphaMissense predicts likely benign (score 0.1284) — an in-silico prediction, not a clinical call.

SLC19A3 p.Val109Ala

c.326T>C · VCV3336378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1284 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1284	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -4.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP 0.75, phastCons 0.95
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	17.86	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 0.0011% South Asian · 1/91,082 alleles

Overall 6.2e-05% 1/1,614,202 alleles · very rare exomes 1/1,461,892 · genomes 0/152,310 · 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: SLC19A3
Protein: p.Val109Ala
Coding: c.326T>C
MANE Select: NM_025243
Type: single nucleotide variant
Location: chr2:227699389 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 109: an α-helix

Full SLC19A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SLC19A3 p.Val109Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
SLC19A3 p.Val109= Likely benign ★ same residue
SLC19A3 c.1172+1G>A Pathogenic/Likely pathogenic ★★ same type
SLC19A3 c.1172+2T>G Pathogenic ★★ same type
SLC19A3 c.1173-1G>A Pathogenic/Likely pathogenic ★★ same type
SLC19A3 c.151-1G>C Likely pathogenic ★★ same type
SLC19A3 c.980-14A>G Pathogenic/Likely pathogenic ★★ same type
SLC19A3 p.Gly23Val Pathogenic/Likely pathogenic ★★ same type

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/slc19a3-p-val109ala (accessed [today's date]).

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