Is SLC19A2 p.Leu259Val (c.775C>G) pathogenic?

SLC19A2 p.Leu259Val (c.775C>G) is classified Uncertain significance in SLC19A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.0168%, mid); Associated with Inborn genetic diseases.

What condition is associated with SLC19A2 p.Leu259Val (c.775C>G)?

SLC19A2 p.Leu259Val (c.775C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SLC19A2 p.Leu259Val (c.775C>G) in the general population?

SLC19A2 p.Leu259Val (c.775C>G) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about SLC19A2 p.Leu259Val (c.775C>G)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

SLC19A2 p.Leu259Val

c.775C>G · rs755125665 · VCV2327058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 20 kb · p 0.054 · regional, not allelic
Overall
CADD	14.33	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 0.0168% Middle Eastern · 1/5,954 alleles

Overall 0.000124% 2/1,613,954 alleles · ultra-rare exomes 2/1,461,660 · genomes 0/152,294 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,954
African / African-American	0.00133%	75,024

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.Leu259Val
Coding: c.775C>G
MANE Select: NM_006996
dbSNP: rs755125665
Type: single nucleotide variant
Location: chr1:169477187 (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

Similar variants

SLC19A2 p.Ala201Gly Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Ala431Ser Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Arg275Cys Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Glu321Lys Uncertain significance ★★ same condition
SLC19A2 p.Gly184Ser Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Gly235Ser Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Gly362Glu Uncertain significance ★★ ⚠ same condition
SLC19A2 p.Gly447Ser Uncertain significance ★★ ⚠ 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-leu259val (accessed [today's date]).

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