UMOD

Chr 16

uromodulin

Also known as: ADMCKD2, ADTKD1, FJHN, HNFJ, HNFJ1, MCKD2, THGP, THP

NCBI Gene: 7369 ENSG00000169344 UniProt: P07911

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is the most abundant protein in mammalian urine under physiological conditions. Its excretion in urine follows proteolytic cleavage of the ectodomain of its glycosyl phosphatidylinosital-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. This protein may act as a constitutive inhibitor of calcium crystallization in renal fluids. Excretion of this protein in urine may provide defense against urinary tract infections caused by uropathogenic bacteria. Defects in this gene are associated with the renal disorders medullary cystic kidney disease-2 (MCKD2), glomerulocystic kidney disease with hyperuricemia and isosthenuria (GCKDHI), and familial juvenile hyperuricemic nephropathy (FJHN). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.25

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

106 unique Pathogenic / Likely Pathogenic· 306 VUS of 624 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — UMOD

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.91 (0.67–1.25)

0≤0.351.4

Missense OE?0.86 (0.78–0.94)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

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

This gene — mechanism propensity

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 · 99% 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, and1

GOFOur data clearly demonstrate a gain-of-toxic function of uromodulin mutations providing insights into the pathogenetic mechanism of the disease.2

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

References

ClinVar Variant Classifications

624 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32

Likely Pathogenic74

VUS306

Likely Benign122

Benign36

Conflicting47

Pathogenic

Likely Pathogenic

306

VUS

122

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	31	0	0	32
Likely Pathogenic	0	74	0	0	74
VUS	32	249	20	5	306
Likely Benign	1	14	37	70	122
Benign	0	2	25	9	36
Conflicting	—				47
Total	34	370	82	84	617

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap UMOD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →