Is SLC2A9 p.Thr125Met (c.374C>T) pathogenic?

SLC2A9 p.Thr125Met (c.374C>T) is classified Likely pathogenic in SLC2A9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-08). AlphaMissense: likely benign (0.1936); Ultra-rare (popmax 0.0783%, amr); Associated with hypouricemia, renal, 2.

What condition is associated with SLC2A9 p.Thr125Met (c.374C>T)?

SLC2A9 p.Thr125Met (c.374C>T) is associated with hypouricemia, renal, 2 (ClinVar).

How common is SLC2A9 p.Thr125Met (c.374C>T) in the general population?

SLC2A9 p.Thr125Met (c.374C>T) is ultra-rare (popmax 0.0783%, amr) (gnomAD).

What do computational predictors say about SLC2A9 p.Thr125Met (c.374C>T)?

AlphaMissense predicts likely benign (score 0.1936) — an in-silico prediction, not a clinical call.

SLC2A9 p.Thr125Met

c.374C>T · rs181509591 · VCV217421

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1936 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0783%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypouricemia, renal, 2

Computational evidence

Protein change
AlphaMissense	0.1936	likely benign ⚠ discordant with ClinVar
REVEL	0.519	indeterminate
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 195 kb · p 0.75 · regional, not allelic
Overall
CADD	26.6	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 0.0783% Admixed American · 47/60,020 alleles

Filtering AF 0.0604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.00502% 81/1,614,034 alleles · ultra-rare exomes 58/1,461,778 · genomes 23/152,256 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0783%	1,277
Remaining individualsnot grpmax-eligible	0.008%	12,501
European (non-Finnish)	0.00237%	42,141
African / African-American	0.00133%	75,016

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.Thr125Met
Coding: c.374C>T
MANE Select: NM_020041
dbSNP: rs181509591
Type: single nucleotide variant
Location: chr4:9996817 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.79 · 7 PDB
Residue 125: a UniProt-annotated variant site (in rhuc2; markedly reduced urate transport activity; decreased protein expression; decreased urate uptake; 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.Thr125= Benign ★★ same residue
SLC2A9 p.Leu75Arg Pathogenic/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-thr125met (accessed [today's date]).

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