UMOD

Chr 16AD

uromodulin

ENSG00000169344 UniProt: P07911 OMIM: 191845

Uromodulin is the most abundant protein in normal urine and functions in the biogenesis and organization of the apical membrane of thick ascending limb epithelial cells in the kidney, where it forms a gel-like structure that contributes to water barrier permeability. Mutations cause tubulointerstitial kidney disease, autosomal dominant, 1 (also known as familial juvenile hyperuricemic nephropathy), which typically presents with hyperuricemia, gout, and progressive chronic kidney disease. This condition follows autosomal dominant inheritance and the gene shows very low constraint to loss-of-function variants (pLI near zero), suggesting the pathogenic variants likely affect protein function rather than simply reducing protein levels.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 1.251 OMIM phenotype

Clinical Summary— UMOD

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Gene-Disease Validity (ClinGen)

autosomal dominant medullary cystic kidney disease with or without hyperuricemia · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 82 VUS of 100 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.25LOEUF

pLI 0.000

Z-score 0.46

OE 0.91 (0.67–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

1.00Z-score

OE missense 0.86 (0.78–0.94)

336 obs / 391.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.91 (0.67–1.25)

0≤0.351.4

Missense OE0.86 (0.78–0.94)

0≤0.61.4

Synonymous OE1.02

0≤1.21.6

LoF obs/exp: 27 / 29.7Missense obs/exp: 336 / 391.6Syn Z: -0.23

0.5771th %ile

GOF

0.6053th %ile

LOF

0.3452th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOF1 literature citation · 100% of P/LP are missense

DN1 literature citation

Literature Evidence

DNIn all measures, the C217G substitution within the D8C domain was more severe than the C126R substitution within EGF-like domain-3. Both substitutions also led to reduced expression of the chaperone protein Hsp70 (see HSPA1A; 140550), trapped wildtype Thp in the ER in a dominant-negative manner, andPMID:22117067

GOFOur data clearly demonstrate a gain-of-toxic function of uromodulin mutations providing insights into the pathogenetic mechanism of the disease.PMID:20472742

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.