Is SLC2A9 p.Pro412Arg (c.1235C>G) pathogenic?

SLC2A9 p.Pro412Arg (c.1235C>G) is classified Uncertain significance in SLC2A9 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.2114); Ultra-rare (popmax 0.0956%, eas); Associated with hypouricemia, renal, 2.

What condition is associated with SLC2A9 p.Pro412Arg (c.1235C>G)?

SLC2A9 p.Pro412Arg (c.1235C>G) is associated with hypouricemia, renal, 2 (ClinVar).

How common is SLC2A9 p.Pro412Arg (c.1235C>G) in the general population?

SLC2A9 p.Pro412Arg (c.1235C>G) is ultra-rare (popmax 0.0956%, eas) (gnomAD).

What do computational predictors say about SLC2A9 p.Pro412Arg (c.1235C>G)?

AlphaMissense predicts likely benign (score 0.2114) — an in-silico prediction, not a clinical call.

SLC2A9 p.Pro412Arg

c.1235C>G · rs121908323 · VCV4598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2114 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0956%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypouricemia, renal, 2

Computational evidence

Protein change
AlphaMissense	0.2114	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -13.78	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 195 kb · p 0.75 · regional, not allelic
Overall
CADD	21.2	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 0.0956% East Asian · 40/41,858 alleles

Filtering AF 0.0721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0639%

Overall 0.00257% 40/1,556,240 alleles · ultra-rare exomes 40/1,403,960 · genomes 0/152,280 · 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: SLC2A9
Protein: p.Pro412Arg
Coding: c.1235C>G
MANE Select: NM_020041
dbSNP: rs121908323
Type: single nucleotide variant
Location: chr4:9887623 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.79 · 7 PDB
Residue 412: a UniProt-annotated variant site (in rhuc2; uncertain significance; according to pubmed:18701466 the variant results in decreased urate uptake, however according to pubmed:22132964 and pubmed:29967582 urate transport activity is not affected; no effect on vmax for urate uptake; no effect on affinity for urate; no effect on protein expression; no effect on localization to plasma membrane; no effect on glucose transport); an α-helix

Full SLC2A9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypouricemia, renal, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC2A9 p.Leu75Arg Pathogenic/Likely pathogenic ★★ same condition
SLC2A9 p.Thr125Met Likely pathogenic ★★ ⚠ same condition
SLC2A9 p.Arg447Trp Uncertain significance ★★ ⚠ same condition
SLC2A9 p.Ile207Val Uncertain significance ★★ ⚠ same condition
SLC2A9 p.Ile335Thr Uncertain significance ★★ ⚠ same condition
SLC2A9 p.Ile375Thr Uncertain significance ★★ ⚠ same condition
SLC2A9 p.Leu17Arg Uncertain significance ★★ ⚠ same condition
SLC2A9 p.Phe471Leu 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/slc2a9-p-pro412arg (accessed [today's date]).

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