GREB1L

Chr 18

GREB1 like retinoic acid receptor coactivator

Also known as: C18orf6, DFNA80, KIAA1772, RHDA3

NCBI Gene: 80000ENSG00000141449UniProt: Q9C091

Acts upstream of or within kidney development. Predicted to be located in membrane. Implicated in autosomal dominant nonsyndromic deafness 80 and renal agenesis. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

UniProtRenal hypodysplasia/aplasia 3
UniProtDeafness, autosomal dominant, 80
548
ClinVar variants
116
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— GREB1L
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
116 Pathogenic / Likely Pathogenic· 244 VUS of 548 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.07LOEUF
pLI 1.000
Z-score 8.30
OE 0.02 (0.01–0.07)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
5.37Z-score
OE missense 0.52 (0.49–0.56)
525 obs / 1003.3 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.02 (0.01–0.07)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.49–0.56)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.76
0≤1.21.6
LoF obs/exp: 2 / 84.2Missense obs/exp: 525 / 1003.3Syn Z: 3.78

ClinVar Variant Classifications

548 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
Likely Pathogenic47
VUS244
Likely Benign146
Benign33
Conflicting9
69
Pathogenic
47
Likely Pathogenic
244
VUS
146
Likely Benign
33
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
4
43
0
69
Likely Pathogenic
19
14
14
0
47
VUS
5
208
26
5
244
Likely Benign
0
18
44
84
146
Benign
0
8
16
9
33
Conflicting
—9
Total4625214398548

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

View in ClinVar →

Protein Context — Lollipop Plot

GREB1L · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GREB1L-related renal hypodysplasia/aplasia

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Toward clinical exomes in diagnostics and management of male infertility.
Lillepea K et al.·Am J Hum Genet
2024
Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications.
Herlin MK·Front Endocrinol (Lausanne)
2024Review
A novel autosomal dominant GREB1L variant associated with non-syndromic hearing impairment in Ghana.
Adadey SM et al.·BMC Med Genomics
2022
Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice.
De Tomasi L et al.·Am J Hum Genet
2017
The expanded spectrum of human disease associated with GREB1L likely includes complex congenital heart disease.
Zhao E et al.·Prenat Diagn
2024
Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome.
Jolly A et al.·HGG Adv
2023
Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment.
Schrauwen I et al.·Genes (Basel)
2020
GREB1L overexpression is associated with good clinical outcomes in breast cancer.
Dong K et al.·Eur J Med Res
2023
A novel de novo synonymous variant in GREB1L impacts the mRNA splicing associated with aplasia of the urogenital system.
Wang Y et al.·Am J Med Genet A
2024Case report
Clinical Exome Sequencing Identifies a Novel Mutation of the GREB1L Gene in a Chinese Family with Renal Agenesis.
Wang A et al.·Genet Test Mol Biomarkers
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools